Heterocyclic containing biphenyl aP2 inhibitors and method

ABSTRACT

aP2 inhibiting compounds are provided having the formula  
                 
 
     wherein R 1 , R 2 , R 3 , R 4 , X-Z and  
                 
 
     are as described herein.  
     A method is also provided for treating diabetes and related diseases, especially Type II diabetes, employing such aP2 inhibitor or a combination of such aP2 inhibitor and another antidiabetic agent such as metformin, glyburide, troglitazone and/or insulin.

FIELD OF THE INVENTION

[0001] The present invention relates to heterocyclic containingbiphenyls which are inhibitors of aP2 and to a method for treatingdiabetes, especially Type II diabetes, as well as hyperglycemia,hyperinsulinemia, obesity, Syndrome X, diabetic complications,atherosclerosis and related diseases, and other chronic inflammatory andautoimmune/inflammatory diseases, employing such heterocyclic containingbiphenyls alone or in combination with one or more types of antidiabeticagents.

BACKGROUND OF THE INVENTION

[0002] Fatty acid binding proteins (FABPs) are small cytoplasmicproteins which bind to fatty acids such as oleic acids which areimportant metabolic fuels and cellular regulators. Dysregulation offatty acid metabolism in adipose tissue is a prominent feature ofinsulin resistance and the transition from obesity to non-insulindependent diabetes mellitus (NIDDM or Type II diabetes).

[0003] aP2 (adipocyte fatty binding protein), an abundant 14.6 KDacytosolic protein in adipocytes, and one of a family of homologousintracellular fatty acid binding proteins (FABPs), is involved in theregulation of fatty acid trafficking in adipocytes and mediates fattyacid fluxes in adipose tissue. G. S. Hotamisligil et al, “Uncoupling ofObesity from Insulin Resistance Through a Targeted Mutation in aP2, theAdipocyte Fatty Acid Binding Protein”, Science, Vol. 274, Nov. 22, 1996,pp. 1377-1379, report that aP2-deficient mice placed on a high fat dietfor several weeks developed dietary obesity, but, unlike control-mice ona similar diet, did not develop insulin resistance or diabetes.Hotamisligil et al conclude that “aP2 is central to the pathway thatlinks obesity to insulin resistance” (Abstract, page 1377).

[0004] DIALOG ALERT DBDR928 dated Jan. 2, 1997, Pharmaprojects No. 5149(Knight-Ridder Information) discloses that a major drug company “isusing virtual screening techniques to identify potential newantidiabetic compounds.” It is reported that “the company is screeningusing aP2, a protein related to adipocyte fatty acid binding protein.”

[0005] U.S. application Serial No. 60/100,677, filed Sep. 17, 1998(attorney file LA24*) discloses a method for treating diabetes employingan aP2 inhibitor.

DESCRIPTON OF THE INVENTION

[0006] In accordance with the present invention, heterocyclic containingbiphenyl compounds are provided which have the structure

[0007] where R¹ and R² are the same or different and are independentlyselected from H, alkyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl,heteroarylalkyl, aralkyl, cycloheteroalkyl and cycloheteroalkylalkyl;

[0008] R³ is selected from hydrogen, halogen, alkyl, alkenyl, alkynyl,alkoxy, cycloalkyl, cycloalkylalkyl, cycloalkenyl, alkylcarbonyl,cycloheteroalkyl, cycloheteroalkylalkyl, cycloalkenylalkyl, haloalkyl,polyhaloalkyl, cyano, nitro, hydroxy, amino, alkanoyl, alkylthio,alkylsulfonyl, alkoxycarbonyl, alkylaminocarbonyl, alkylcarbonylamino,alkylcarbonyloxy, alkylaminosulfonyl, alkylamino, dialkylamino, alloptionally substituted through available carbon atoms with 1, 2, 3, 4 or5 groups selected from hydrogen, halo, alkyl, polyhaloalkyl, alkoxy,haloalkoxy, polyhaloalkoxy, alkoxycarbonyl, alkenyl, alkynyl,cycloalkyl, cycloalkylalkyl, cycloheteroalkyl, cycloheteroalkylalkyl,hydroxy, hydroxyalkyl, nitro, cyano, amino, substituted amino,alkylamino, dialkylamino, thiol, alkylthio, alkylcarbonyl, acyl,alkoxycarbonyl, aminocarbonyl, alkynylaminocarbonyl, alkylaminocarbonyl,alkenylaminocarbonyl, alkylcarbonyloxy, alkylcarbonylamino,alkoxycarbonylamino, alkylsulfonyl, aminosulfinyl, aminosulfonyl,alkylsulfinyl, sulfonamido or sulfonyl;

[0009] R⁴ is selected from hydrogen, halogen, alkyl, alkenyl, alkynyl,alkoxy, aryl, heteroaryl, arylalkyl, heteroarylalkyl, arylalkenyl,arylalkynyl, cycloalkyl, cycloalkylalkyl, polycycloalkyl,polycycloalkylalkyl, cycloalkenyl, cycloalkynyl, alkylcarbonyl,arylcarbonyl, cycloheteroalkyl, cycloheteroalkylalkyl,cycloalkenylalkyl, polycycloalkenyl, polycycloalkenylalkyl,polycycloalkynyl, polycycloalkynylalkyl, haloalkyl, polyhaloalkyl,cyano, nitro, hydroxy, amino, alkanoyl, aroyl, alkylthio, alkylsulfonyl,arylsulfonyl, alkoxycarbonyl, aryloxycarbonyl, alkylaminocarbonyl,arylaminocarbonyl, alkylcarbonylamino, alkylcarbonyloxy,alkylaminosulfonyl, arylaminosulfonyl, alkylamino, dialkylamino, alloptionally substituted through available carbon atoms with 1, 2, 3, 4 or5 groups selected from hydrogen, halo, alkyl, haloalkyl, polyhaloalkyl,alkoxy, haloalkoxy, polyhaloalkoxy, alkoxycarbonyl, alkenyl, alkynyl,cycloalkyl, cycloalkylalkyl, cycloheteroalkyl, cycloheteroalkylalkyl,aryl, heteroaryl, arylalkyl, arylcycloalkyl, arylalkenyl, arylalkynyl,aryloxy, aryloxyalkyl, arylalkoxy, arylazo, heteroaryloxo,heteroarylalkyl, heteroarylalkenyl, heteroaryloxy, hydroxy,hydroxyalkyl, nitro, cyano, amino, substituted amino, alkylamino,dialkylamino, thiol, alkylthio, arylthio, heteroarylthio, arylthioalkyl,alkylcarbonyl, arylcarbonyl, acyl, arylaminocarbonyl, alkoxycarbonyl,aminocarbonyl, alkynylaminocarbonyl, alkylaminocarbonyl,alkenylaminocarbonyl, alkylcarbonyloxy, arylcarbonyloxy,alkylcarbonylamino, arylcarbonylamino, alkoxycarbonylamino,arylsulfinyl, arylsulfinylalkyl, arylsulfonyl, alkylsulfonyl,aminosulfinyl, aminosulfonyl, arylsulfonylamino,heteroarylcarbonylamino, heteroarylsulfinyl, heteroarylthio,heteroarylsulfonyl, alkylsulfinyl, sulfonamido or sulfonyl;

[0010] X is a bond or a linker group selected from (CH₂)_(n),O(CH₂)_(n), S(CH₂)_(n), NHCO, CH═CH, cycloalkylene or N(R⁵) (CH₂)_(n),(where n=0-5 and R⁵ is H, alkyl, or alkanoyl);

[0011] Z is CO₂H or tetrazole of the formula

[0012] or its tautomer; and the group

[0013] represents a heterocyclic group (including heteroaryl andcycloheteroalkyl groups) preferably containing 5-members within the ringand containing preferably 1-3 heteroatoms within the ring, and which mayfurther optionally include one or two substituents which are alkyl,alkenyl, hydroxyalkyl, keto, carboxyalkyl, carboxy, cycloalkyl, alkoxy,formyl, alkanoyl, alkoxyalkyl or alkoxycarboxyl;

[0014] with the provisos that (1) n≠o when Z is CO₂H and X isO(CH₂)_(n), S(CH₂)_(n) or N(R⁵) (CH₂)_(n)); and

[0015] (2) when

[0016] is

[0017] then X-Z may not be O-lower alkylene-CO₂H or —O-loweralkylene-CO₂alkyl when R¹ and R² are both aryl or substituted aryl andR³ and R⁴ are each hydrogen;

[0018] and including pharmaceutically acceptable salts thereof, andprodrug esters thereof, and all stereoisomers thereof.

[0019] In addition, in accordance with the present invention, a methodis provided for treating diabetes, especially Type II diabetes, andrelated diseases such as insulin resistance, hyperglycemia,hyperinsulinemia, elevated blood levels of fatty acids or glycerol,obesity, hypertriglyceridemia, Syndrome X, diabetic complications,atherosclerosis and other chronic inflammatory andautoimmune/inflammatory diseases, wherein a therapeutically effectiveamount of a compound of structure I (which inhibits aP2) is administeredto a human patient in need of treatment.

[0020] The term “chronic inflammatory and autoimmune/inflammatorydiseases” referred to above includes inflammatory bowel diseases, suchas Crohn's disease and ulcerative colitis, rheumatoid arthritis, chronicobstructive pulmonary disease, emphysema, systemic lupus erythematosis,and other disease states involving tissue injury-, necrosis-, and/orinfection-induced imbalanced inflammation associated with macrophage andleukocyte over-stimulation and excessive or dysregulated release ofcellular mediators.

[0021] In addition, in accordance with the present invention, a methodis provided for treating chronic and autoimmune/inflammatory diseasesincluding inflammatory bowel diseases such as Crohn's disease andulcerative colitis, rheumatoid arthritis, chronic obstructive pulmonarydisease, emphysema, systemic lupus erythematosis, and other diseasestates involving tissue injury-, necrosis-, and/or infection-inducedimbalanced inflammation associated with macrophage and leukocyteover-stimulation and excessive or dysregulated release of cellularmediators, wherein a therapeutically effective amount of an aP2inhibitor is administered to a human patient in need of treatment.

[0022] In addition to compounds of formula I, other aP2 inhibitorsuseful in carrying out the above method for treating chronicinflammatory and autoimmune/inflammatory diseases are disclosed in U.S.application Ser. No. 09/390,275, filed Sep. 7, 1999 (file LA24a), whichis incorporated herein by reference.

[0023] The conditions, diseases, and maladies collectively referred toas “Syndrome X” (also known as Metabolic Syndrome) are detailed inJohannsson J. Clin. Endocrinol. Metab., 82, 727-34 (1997).

[0024] The conditions, diseases and maladies collectively referred to as“diabetic complications” include retinopathy, neuopathy and nephropathy,and other known complications of diabetes.

[0025] In addition, in accordance with the present invention, a methodis provided for treating diabetes and related diseases as defined aboveand hereinafter, as well as obesity, hypertriglyceridemia, Syndrome X,diabetic complications and other chronic inflammatory andautoimmune/inflammatory diseases, wherein a therapeutically effectiveamount of a combination of a compound of structure 1 and 1, 2, 3 or moreother types of therapeutic agents is administered to a human patient inneed of treatment.

[0026] The term “other type of therapeutic agents” as employed hereinrefers to one or more antidiabetic agents (other than aP2 inhibitors offormula I), one or more anti-obesity agents, one or more lipid-loweringagents (including anti-atherosclerosis agents), one or moreanti-hypertensive agents, one or more anti-platelet agents, and/or oneor more anti-infective agents.

[0027] In the above method of the invention, the compound of structure Iwill be employed in a weight ratio to the other type of therapeuticagent (depending upon its mode of operation) within the range from about0.01:1 to about 500:1, preferably from about 0.1:1 to about 100:1.

[0028] Examples of the group

[0029] include (but are not limited to) heteroaryl groups andcycloheteroalkyl groups as defined herein and preferably include thefollowing:

[0030] where R⁸ is selected from H, alkyl, haloalkyl, hydroxyalkyl,alkoxyalkyl, or alkenyl, and

[0031] R⁹ and R^(9′) are the same or different and are selectedindependently from H, alkyl, alkoxy, alkenyl, formyl, CO₂H, CO₂(loweralkyl), hydroxyalkyl, alkoxyalkyl, CO(alkyl), carboxylalkyl, haloalkyl,alkenyl or cycloalkyl.

[0032] With respect to the R⁸, R⁹ and R⁹ groups, alkyl by itself or aspart of another group will preferably contain 1 to 6 carbons.

[0033] Examples of X-Z moieties include (but are not limited to)

[0034] Preferred are compounds of formula I where

[0035] (where R⁸ is hydrogen, alkyl, fluoroalkyl or alkoxyalkyl, andwhere R⁹ is hydrogen, alkyl, fluoroalkyl, alkoxy or hydroxyalkyl).

[0036] R¹ and R² are each phenyl, substituted phenyl or cycloalkyl; R³and R⁴ are the same or different are independently selected from H,halo, alkyl or alkoxy; X is OCH₂, NHCH₂, CH₂ or CH₂CH₂; and Z is CO₂H ortetrazole.

[0037] More preferred are compounds of formula I where

[0038] R¹ and R² are each phenyl; R³ and R⁴ are each H; X is OCH₂, CH₂or NHCH₂; and Z is CO₂H or tetrazole.

DETAILED DESCRIPTION OF THE INVENTION

[0039] Compounds of the invention of general structure I may besynthesized from intermediate II as shown in the schemes set out below.The groups R¹, R², R³, and R⁴, in intermediate II, are the same asdescribed above with respect to the formula I compounds of the inventionwhile A is a precursor to X-Z and is detailed below.

[0040] where R¹⁰ is lower alkyl or benzyl.

[0041] The biphenyl portion of the molecule may be prepared by reactionof compound III with substituted aryl IV via Stille or Suzuki typecoupling to give compounds of the type V.

[0042] where W is B(OH)₂, SnBu₃, or ZnBr or ZnCl and G is Cl, Br, I, orOTf or G is B(OH)₂ or SnBu₃ and W is Cl, Br, I, or OTf and E may be CHO,CN, CO₂R¹⁰, OH, N(R⁵)H, NO₂, SR¹⁰, OR¹⁰, OSi(R¹⁰)₃, or preferably X-Z ora protected variant thereof and where R¹¹ is CO₂R¹⁰, CHO, CN,—NH—N═C(R²)(CH₂R¹), NH₂, or —CONH—N═CH(R²)

[0043] with the proviso that when W or G is ZnBr or ZnCl, E or R¹¹ maynot be a reactive group such as CHO.

[0044] Compound V, depicted below where Y is

[0045] can be utilized to make heterocycles of the type VIA-VIN bystandard methods described in the literature, for example, as shownbelow.

[0046] Alternately, and in some cases more preferably, compounds of thetype VII may be converted to the desired heterocycles by theseaforementioned methodologies and subsequently converted to compounds oftype II via biphenyl coupling reactions.

[0047] with the proviso that when W is ZnCl or ZnBr, E cannot be areactive group such as CHO.

[0048] Unless otherwise indicated, the term “lower alkyl”, “alkyl” or“alk” as employed herein alone or as part of another group includes bothstraight and branched chain hydrocarbons, containing 1 to 20 carbons,preferably 1 to 10 carbons, more preferably 1 to 8 carbons, in thenormal chain, such as methyl, ethyl, propyl, isopropyl, butyl, t-butyl,isobutyl, pentyl, hexyl, isohexyl, heptyl, 4,4-dimethylpentyl, octyl,2,2,4-trimethyl-pentyl, nonyl, decyl, undecyl, dodecyl, the variousbranched chain isomers thereof, and the like as well as such groupsincluding 1 to 4 substituents such as halo, for example F, Br, Cl or Ior CF₃, alkoxy, aryl, aryloxy, aryl(aryl) or diaryl, arylalkyl,arylalkyloxy, alkenyl, cycloalkyl, cycloalkylalkyl, cycloalkylalkyloxy,amino, hydroxy, hydroxyalkyl, acyl, heteroaryl, heteroaryloxy,heteroarylalkyl, heteroarylalkoxy, aryloxyalkyl, aryloxyaryl,alkylamido, alkanoylamino, arylcarbonylamino, nitro, cyano, thiol,haloalkyl, trihaloalkyl and/or alkylthio and/or any of the R³ groups orsubstituents for R³.

[0049] Unless otherwise indicated, the term “cycloalkyl” as employedherein alone or as part of another group includes saturated or partiallyunsaturated (containing 1 or 2 double bonds) cyclic hydrocarbon groupscontaining 1 to 3 rings, including monocyclicalkyl, bicyclicalkyl andtricyclicalkyl, containing a total of 3 to 20 carbons forming the rings,preferably 3 to 10 carbons, forming the ring and which may be fused to 1or 2 aromatic rings as described for aryl, which include cyclopropyl,cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclodecyland cyclododecyl, cyclohexenyl,

[0050] any of which groups may be optionally substituted with 1 to 4substituents such as halogen, alkyl, alkoxy, hydroxy, aryl, aryloxy,arylalkyl, cycloalkyl, alkylamido, alkanoylamino, oxo, acyl,arylcarbonylamino, amino, nitro, cyano, thiol and/or alkylthio and/orany of the R⁴ groups or substituents for R⁴.

[0051] The term “cycloalkenyl” as employed herein alone or as part ofanother group refers to cyclic hydrocarbons containing 3 to 12 carbons,preferably 5 to 10 carbons and 1 or 2 double bonds. Exemplarycycloalkenyl groups include cyclopentenyl, cyclohexenyl, cycloheptenyl,cyclooctenyl, cyclohexadienyl, and cycloheptadienyl, which may beoptionally substituted as defined for cycloalkyl.

[0052] The term “cycloalkylene” as employed herein refers to a“cycloalkyl” group which includes free bonds and thus is a linking groupsuch as

[0053] and the like, and may optionally be substituted as defined abovefor “cycloalkyl”.

[0054] The term “alkanoyl” as used herein alone or as part of anothergroup refers to alkyl linked to a carbonyl group.

[0055] Unless otherwise indicated, the term “lower alkenyl” or “alkenyl”as used herein by itself or as part of another group refers to straightor branched chain radicals of 2 to 20 carbons, preferably 2 to 12carbons, and more preferably 1 to 8 carbons in the normal chain, whichinclude one to six double bonds in the normal chain, such as vinyl,2-propenyl, 3-butenyl, 2-butenyl, 4-pentenyl, 3-pentenyl, 2-hexenyl,3-hexenyl, 2-heptenyl, 3-heptenyl, 4-heptenyl, 3-octenyl, 3-nonenyl,4-decenyl, 3-undecenyl, 4-dodecenyl, 4,8,12-tetradecatrienyl, and thelike, and which may be optionally substituted with 1 to 4 substituents,namely, halogen, haloalkyl, alkyl, alkoxy, alkenyl, alkynyl, aryl,arylalkyl, cycloalkyl, amino, hydroxy, heteroaryl, cycloheteroalkyl,alkanoylamino, alkylamido, arylcarbonyl-amino, nitro, cyano, thiol,alkylthio and/or any of the R³ groups, or the R³ substituents set outherein.

[0056] Unless otherwise indicated, the term “lower alkynyl” or “alkynyl”as used herein by itself or as part of another group refers to straightor branched chain radicals of 2 to 20 carbons, preferably 2 to 12carbons and more preferably 2 to 8 carbons in the normal chain, whichinclude one triple bond in the normal chain, such as 2-propynyl,3-butynyl, 2-butynyl, 4-pentynyl, 3-pentynyl, 2-hexynyl, 3-hexynyl,2-heptynyl, 3-heptynyl, 4-heptynyl, 3-octynyl, 3-nonynyl, 4-decynyl,3-undecynyl, 4-dodecynyl and the like, and which may be optionallysubstituted with 1 to 4 substituents, namely, halogen, haloalkyl, alkyl,alkoxy, alkenyl, alkynyl, aryl, arylalkyl, cycloalkyl, amino,heteroaryl, cycloheteroalkyl, hydroxy, alkanoylamino, alkylamido,arylcarbonylamino, nitro, cyano, thiol, and/or alkylthio, and/or any ofthe R³ groups, or the R³ substituents set out herein.

[0057] The terms “arylalkenyl” and “arylalkynyl” as used alone or aspart of another group refer to alkenyl and alkynyl groups as describedabove having an aryl substituent.

[0058] Where alkyl groups as defined above have single bonds forattachment to other groups at two different carbon atoms, they aretermed “alkylene” groups and may optionally be substituted as definedabove for “alkyl”.

[0059] Where alkenyl groups as defined above and alkynyl groups asdefined above, respectively, have single bonds for attachment at twodifferent carbon atoms, they are termed “alkenylene groups” and“alkynylene groups”, respectively, and may optionally be substituted asdefined above for “alkenyl” and “alkynyl”.

[0060] Suitable alkylene, alkenylene or alkynylene groups (CH₂)_(n) or(CH₂)_(p) (where, p is 1 to 8, preferably 1 to 5, and n is 1 to 5,preferably 1 to 3, which includes alkylene, alkenylene or alkynylenegroups) as defined herein, may optionally include 1, 2, or 3substituents which include alkyl, alkenyl, halogen, cyano, hydroxy,alkoxy, amino, thioalkyl, keto, C₃-C₆ cycloalkyl, alkylcarbonylamino oralkylcarbonyloxy.

[0061] Examples of (CH2)_(n) or (CH₂)_(p), alkylene, alkenylene andalkynylene include

[0062] The term “halogen” or “halo” as used herein alone or as part ofanother group refers to chlorine, bromine, fluorine, and iodine as wellas CF₃, with chlorine or fluorine being preferred.

[0063] The term “metal ion” refers to alkali metal ions such as sodium,potassium or lithium and alkaline earth metal ions such as magnesium andcalcium, as well as zinc and aluminum.

[0064] Unless otherwise indicated, the term “aryl” as employed hereinalone or as part of another group refers to monocyclic and bicyclicaromatic groups containing 6 to 10 carbons in the ring portion (such asphenyl or naphthyl including 1-naphthyl and 2-naphthyl) and mayoptionally include one to three additional rings fused to a carbocyclicring or a heterocyclic ring (such as aryl, cycloalkyl, heteroaryl orcycloheteroalkyl rings for example

[0065] and may be optionally substituted through available carbon atomswith 1, 2, or 3 groups selected from hydrogen, halo, haloalkyl, alkyl,haloalkyl, alkoxy, haloalkoxy, alkenyl, trifluoromethyl,trifluoromethoxy, alkynyl, cycloalkyl-alkyl, cycloheteroalkyl,cycloheteroalkylalkyl, aryl, heteroaryl, arylalkyl, aryloxy,aryloxyalkyl, arylalkoxy, arylthio, arylazo, heteroarylalkyl,heteroarylalkenyl, heteroarylheteroaryl, heteroaryloxy, hydroxy, nitro,cyano, amino, substituted amino wherein the amino includes 1 or 2substituents (which are alkyl, aryl or any of the other aryl compoundsmentioned in the definitions), thiol, alkylthio, arylthio,heteroarylthio, arylthioalkyl, alkoxyarylthio, alkylcarbonyl,arylcarbonyl, alkyl-aminocarbonyl, arylaminocarbonyl, alkoxycarbonyl,aminocarbonyl, alkylcarbonyloxy, arylcarbonyloxy, alkylcarbonylamino,arylcarbonylamino, arylsulfinyl, arylsulfinylalkyl, arylsulfonylamino orarylsulfon-aminocarbonyl and/or any of the R⁴ groups or the R⁴substituents set out herein.

[0066] Unless otherwise indicated, the term “lower alkoxy”, “alkoxy”,“aryloxy” or “aralkoxy” as employed herein alone or as part of anothergroup includes any of the above alkyl, aralkyl or aryl groups linked toan oxygen atom.

[0067] Unless otherwise indicated, the term “substituted amino” asemployed herein alone or as part of another group refers to aminosubstituted with one or two substituents, which may be the same ordifferent, such as alkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl,cycloheteroalkyl, cycloheteroalkylalkyl, cycloalkyl, cycloalkylalkyl,haloalkyl, hydroxyalkyl, alkoxyalkyl or thioalkyl. These substituentsmay be further substituted with a carboxylic acid and/or any of the R⁴groups or R⁴ substituents thereof as set out above. In addition, theamino substituents may be taken together with the nitrogen atom to whichthey are attached to form 1-pyrrolidinyl, 1-piperidinyl, 1-azepinyl,4-morpholinyl, 4-thiamorpholinyl, 1-piperazinyl, 4-alkyl-1-piperazinyl,4-arylalkyl-1-piperazinyl, 4-diarylalkyl-1-piperazinyl, 1-pyrrolidinyl,1-piperidinyl, or 1-azepinyl, optionally substituted with alkyl, alkoxy,alkylthio, halo, trifluoromethyl or hydroxy.

[0068] Unless otherwise indicated, the term “lower alkylthio”,alkylthio”, “arylthio” or “aralkylthio” as employed herein alone or aspart of another group includes any of the above alkyl, aralkyl or arylgroups linked to a sulfur atom.

[0069] Unless otherwise indicated, the term “lower alkylamino”,“alkylamino”, “arylamino”, or “arylalkylamino” as employed herein aloneor as part of another group includes any of the above alkyl, aryl orarylalkyl groups linked to a nitrogen atom.

[0070] Unless otherwise indicated, the term “acyl” as employed herein byitself or part of another group, as defined herein, refers to an organicradical linked to a carbonyl

[0071] group; examples of acyl groups include any of the R³ groupsattached to a carbonyl, such as alkanoyl, alkenoyl, aroyl, aralkanoyl,heteroaroyl, cycloalkanoyl, cycloheteroalkanoyl and the like.

[0072] Unless otherwise indicated, the term “cycloheteroalkyl” as usedherein alone or as part of another group refers to a 5-, 6- or7-membered saturated or partially unsaturated ring which includes 1 to 2hetero atoms such as nitrogen, oxygen and/or sulfur, linked through acarbon atom or a heteroatom, where possible, optionally via the linker(CH₂)_(p) (where p is 1, 2 or 3), such as

[0073] and the like. The above groups may include 1 to 4 substituentssuch as alkyl, halo, oxo and/or any of of the R⁴ groups, or the R⁴substituents set out herein. In addition, any of the cycloheteroalkylrings can be fused to a cycloalkyl, aryl, heteroaryl or cycloheteroalkylring.

[0074] Unless otherwise indicated, the term “heteroaryl” as used hereinalone or as part of another group refers to a 5- or 6-membered aromaticring which includes 1, 2, 3 or 4 hetero atoms such as nitrogen, oxygenor sulfur, and such rings fused to an aryl, cycloalkyl, heteroaryl orcycloheteroalkyl ring (e.g. benzothiophenyl, indolyl), and includespossible N-oxides. The heteroaryl group may optionally include 1 to 4substituents such as any of the R⁴ groups or the R⁴ substituents set outabove. Examples of heteroaryl groups include the following:

[0075] and the like.

[0076] The term “cycloheteroalkylalkyl” as used herein alone or as partof another gorup refers to cycloheteroalkyl groups as defined abovelinked through a C atom or heteroatom to a (CH₂)_(p) chain.

[0077] The term “heteroarylalkyl” or “heteroarylalkenyl” as used hereinalone or as part of another group refers to a heteroaryl group asdefined above linked through a C atom or heteroatom to a —(CH₂)_(p)—chain, alkylene or alkenylene as defined above.

[0078] The term “polyhaloalkyl” as used herein refers to an “alkyl”group as defined above which includes from 2 to 9, preferably from 2 to5, halo substituents, such as F or Cl, preferably F, such as CF₃CH₂, CF₃or CF₃CF₂CH₂.

[0079] The term “polyhaloalkyloxy” as used herein refers to an “alkoxy”or “alkyloxy” group as defined above which includes from 2 to 9,preferably from 2 to 5, halo substituents, such as F or Cl, preferablyF, such as CF₃CH₂O, CF₃O or CF₃CF₂CH₂O.

[0080] The term “prodrug esters” as employed herein includes prodrugesters which are known in the art for carboxylic acids such as similarcarboxylic acid esters such as methyl, ethyl benzyl and the like. Otherexamples include the following groups: (1-alkanoyloxy)alkyl such as,

[0081] wherein R^(a), R^(b) and R^(c) are H, alkyl, aryl or aryl-alkyl;however R^(a)O cannot be HO, and where Z¹ is

[0082] (where X is previously defined).

[0083] Examples of such prodrug esters include

[0084] CH₃CO₂CH₂—

[0085] t-C₄H₉CO₂CH₂—, or

[0086] Other examples of suitable prodrug esters include

[0087] wherein R^(a) can be H, alkyl (such as methyl or t-butyl),arylalkyl (such as benzyl) or aryl (such as phenyl); R^(d) is H, alkyl,halogen or alkoxy, R^(e) is alkyl, aryl, arylalkyl or alkoxyl, and n₁ is0, 1 or 2.

[0088] Where the compounds of structure I are in acid form it may form apharmaceutically acceptable salt such as alkali metal salts such aslithium, sodium or potassium, alkaline earth metal salts such as calciumor magnesium as well as zinc or aluminum and other cations such asammonium, choline, diethanolamine, ethylenediamine, t-butylamine,t-octylamine, dehydroabietylamine.

[0089] All stereoisomers of the compounds of the instant invention arecontemplated, either in admixture or in pure or substantially pure form.The compounds of the present invention can have asymmetric centers atany of the carbon atoms including any one or the R substituents.Consequently, compounds of formula I can exist in enantiomeric ordiastereomeric forms or in mixtures thereof. The processes forpreparation can utilize racemates, enantiomers or diastereomers asstarting materials. When diastereomeric or enantiomeric products areprepared, they can be separated by conventional methods for example,chromatographic or fractional crystallization.

[0090] Where desired, the compounds of structure I may be used incombination with one or more other types of therapeutic agents which maybe administered orally in the same dosage form, in a separate oraldosage form or by injection.

[0091] The other type of therapeutic agent which may be optionallyemployed in combination with the aP2 inhibitor of formula I may be 1,2,3or more antidiabetic agents or antihyperglycemic agents includinginsulin secretagogues or insulin sensitizers, or other antidiabeticagents preferably having a mechanism of action different from aP2inhibition and may include biguamides, sulfonyl ureas, glucosidaseinhibitors, PPAR γ agonists, such as thiazolidinediones, SGLT2inhibitors, PPAR α/γ dual agonists, dipeptidyl peptidase IV (DP4)inhibitors, and/or meglitinides, as well as insulin, and/orglucagon-like peptide-1 (GLP-1).

[0092] It is believed that the use of the compounds of structure I incombination with 1, 2, 3 or more other antidiabetic agents producesantihyperglycemic results greater than that possible from each of thesemedicaments alone and greater than the combined additiveanti-hyperglycemic effects produced by these medicaments.

[0093] The other antidiabetic agent may be an oral antihyperglycemicagent preferably a biguamide such as metformin or phenformin or saltsthereof, preferably metformin HCl.

[0094] Where the other antidiabetic agent is a biguamide, the compoundsof structure I will be employed in a weight ratio to biguamide withinthe range from about 0.01:1 to about 100:1, preferably from about 0.1:1to about 5:1.

[0095] The other antidiabetic agent may also preferably be a sulfonylurea such as glyburide (also known as glibenclamide), glimepiride(disclosed in U.S. Pat. No. 4,379,785), glipizide, gliclazide orchlorpropamide, other known sulfonylureas or other antihyperglycemicagents which act on the ATP-dependent channel of the β-cells, withglyburide and glipizide being preferred, which may be administered inthe same or in separate oral dosage forms.

[0096] The compounds of structure I will be employed in a weight ratioto the sulfonyl urea in the range from about 0.01:1 to about 100:1,preferably from about 0.2:1 to about 10:1.

[0097] The oral antidiabetic agent may also be a glucosidase inhibitorsuch as acarbose (disclosed in U.S. Pat. No. 4,904,769) or miglitol(disclosed in U.S. Pat. No. 4,639,436), which may be administered in thesame or in a separate oral dosage forms.

[0098] The compounds of structure I will be employed in a weight ratioto the glucosidase inhibitor within the range from about 0.01:1 to about100:1, preferably from about 0.5:1 to about 50:1.

[0099] The compounds of structure I may be employed in combination witha PPAR γ agonist such as a thiazolidinedione oral anti-diabetic agent orother insulin sensitizers (which has an insulin sensitivity effect inNIDDM patients) such as troglitazone (Warner-Lambert's Rezulin®,disclosed in U.S. Pat. No. 4,572,912), rosiglitazone (SKB), pioglitazone(Takeda), Mitsubishi's MCC-555 (disclosed in U.S. Pat. No. 5,594,016),Glaxo-Welcome's GL-262570, englitazone (CP-68722, Pfizer) ordarglitazone (CP-86325, Pfizer, isaglitazone (MIT/J&J), JTT-501(JPNT/P&U), L-895645 (Merck), R-119702 (Sankyo/WL), NN-2344 (Dr.Reddy/NN), or YM-440 (Yamanouchi), preferably rosiglitazone andpioglitazone.

[0100] The compounds of structure I will be employed in a weight ratioto the thiazolidinedione in an amount within the range from about 0.01:1to about 100:1, preferably from about 0.2:1 to about 10:1.

[0101] The sulfonyl urea and thiazolidinedione in amounts of less thanabout 150 mg oral antidiabetic agent may be incorporated in a singletablet with the compounds of structure I.

[0102] The compounds of structure I may also be employed in combinationwith a antihyperglycemic agent such as insulin or with glucagon-likepeptide-1 (GLP-1) such as GLP-1(1-36) amide, GLP-1(7-36) amide,GLP-1(7-37) (as disclosed in U.S. Pat. No. 5,614,492 to Habener, thedisclosure of which is incorporated herein by reference), as well asAC2993 (Amylen) and LY-315902 (Lilly), which may be administered viainjection, intranasal, or by transdermal or buccal devices.

[0103] Where present, metformin, the sulfonyl ureas, such as glyburide,glimepiride, glipyride, glipizide, chlorpropamide and gliclazide and theglucosidase inhibitors acarbose or miglitol or insulin (injectable,pulmonary, buccal, or oral) may be employed in formulations as describedabove and in amounts and dosing as indicated in the Physician's DeskReference (PDR).

[0104] Where present, metformin or salt thereof may be employed inamounts within the range from about 500 to about 2000 mg per day whichmay be administered in single or divided doses one to four times daily.

[0105] Where present, the thiazolidinedione anti-diabetic agent may beemployed in amounts within the range from about 0.01 to about 2000mg/day which may be administered in single or divided doses one to fourtimes per day.

[0106] Where present insulin may be employed in formulations, amountsand dosing as indicated by the Physician's Desk Reference.

[0107] Where present GLP-1 peptides may be administered in oral buccalformulations, by nasal administration or parenterally as described inU.S. Pat. Nos. 5,346,701 (TheraTech), 5,614,492 and 5,631,224 which areincorporated herein by reference.

[0108] The other antidiabetic agent may also be a PPAR α/γ dual agonistsuch as AR-HO39242 (Astra/Zeneca), GW-409544 (Glaxo-Wellcome), KRP297(Kyorin Merck) as well as those disclosed by Murakami et al, “A NovelInsulin Sensitizer Acts As a Coligand for PeroxisomeProliferation—Activated Receptor Alpha (PPAR alpha) and PPAR gamma.Effect on PPAR alpha Activation on Abnormal Lipid Metabolism in Liver ofZucker Fatty Rats”, Diabetes 47, 1841-1847 (1998), and in U.S.provisional application No. 60/155,400, filed Sep. 22, 1999, (attorneyfile LA29) the disclosure of which is incorporated herein by reference,employing dosages as set out therein, which compounds designated aspreferred are preferred for use herein.

[0109] The other antidiabetic agent may be an SGLT2 inhibitor such asdisclosed in U.S. provisional application No. 60/158,773, filed Oct. 12,1999 (attorney file LA49), employing dosages as set out herein.Preferred are the compounds designated as preferred in the aboveapplication.

[0110] The other antidiabetic agent may be a DP4 inhibitor such asdisclosed in WO99/38501, WO99/46272, WO99/67279 (PROBIODRUG), WO99/67278(PROBIODRUG), WO99/61431 (PROBIODRUG), NVP-DPP728A(1-[[[2-[(5-cyanopyridin-2-yl)amino]ethyl]amino]acetyl]-2-cyano-(S)-pyrrolidine)(Novartis) (preferred) as disclosed by Hughes et al, Biochemistry,38(36), 11597-11603, 1999, TSL-225(tryptophyl-1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid (disclosedby Yamada et al, Bioorg. & Med. Chem. Lett. 8 (1998) 1537-1540,2-cyanopyrrolidides and 4-cyanopyrrolidides as disclosed by Ashworth etal, Bioorg. & Med. Chem. Lett., Vol. 6, No. 22, pp 1163-1166 and2745-2748 (1996) employing dosages as set out in the above references.

[0111] The meglitinide which may optionally be employed in combinationwith the compound of formula I of the invention may be repaglinide,nateglinide (Novartis) or KAD1229 (PF/Kissei), with repaglinide beingpreferred.

[0112] The aP2 inhibitor of formula I will be employed in a weight ratioto the meglitinide, PPAR γ agonist, PPAR α/γ dual agonist, SGLT2inhibitor or DP4 inhibitor within the range from about 0.01:1 to about100:1, preferably from about 0.2:1 to about 10:1.

[0113] The hypolipidemic agent or lipid-lowering agent which may beoptionally employed in combination with the compounds of formula I ofthe invention may include 1, 2, 3 or more MTP inhibitors, HMG CoAreductase inhibitors, squalene synthetase inhibitors, fibric acidderivatives, ACAT inhibitors, lipoxygenase inhibitors, cholesterolabsorption inhibitors, ileal Na⁺/bile acid cotransporter inhibitors,upregulators of LDL receptor activity, bile acid sequestrants, and/ornicotinic acid and derivatives thereof.

[0114] MTP inhibitors employed herein include MTP inhibitors disclosedin U.S. Pat. No. 5,595,872, U.S. Pat. No. 5,739,135, U.S. Pat. No.5,712,279, U.S. Pat. No. 5,760,246, U.S. Pat. No. 5,827,875, U.S. Pat.No. 5,885,983 and U.S. application Ser. No. 09/175,180 filed Oct. 20,1998, now U.S. Pat. No. 5,962,440. Preferred are each of the preferredMTP inhibitors disclosed in each of the above patents and applications.

[0115] All of the above U.S. patents and applications are incorporatedherein by reference.

[0116] Most preferred MTP inhibitors to be employed in accordance withthe present invention include preferred MTP inhibitors as set out inU.S. Pat. Nos. 5,739,135 and 5,712,279, and U.S. Pat. No. 5,760,246.

[0117] The most preferred MTP inhibitor is9-[4-[4-[[2-(2,2,2-Trifluoroethoxy)benzoyl]amino]-1-piperidinyl]butyl]-N-(2,2,2-trifluoroethyl)-9H-fluorene-9-carboxamide

[0118] The hypolipidemic agent may be an HMG CoA reductase inhibitorwhich includes, but is not limited to, mevastatin and related compoundsas disclosed in U.S. Pat. No. 3,983,140, lovastatin (mevinolin) andrelated compounds as disclosed in U.S. Pat. No. 4,231,938, pravastatinand related compounds such as disclosed in U.S. Pat. No. 4,346,227,simvastatin and related compounds as disclosed in U.S. Pat. Nos.4,448,784 and 4,450,171. Other HMG CoA reductase inhibitors which may beemployed herein include, but are not limited to, fluvastatin, disclosedin U.S. Pat. No. 5,354,772, cerivastatin disclosed in U.S. Pat. Nos.5,006,530 and 5,177,080, atorvastatin disclosed in U.S. Pat. Nos.4,681,893, 5,273,995, 5,385,929 and 5,686,104, atavastatin(Nissan/Sankyo's nisvastatin (NK-104)) disclosed in U.S. Pat. No.5,011,930, Shionogi-Astra/Zeneca visastatin (ZD-4522) disclosed in U.S.Pat. No. 5,260,440, and related statin compounds disclosed in U.S. Pat.No. 5,753,675, pyrazole analogs of mevalonolactone derivatives asdisclosed in U.S. Pat. No. 4,613,610, indene analogs of mevalonolactonederivatives as disclosed in PCT application WO 86/03488,6-[2-(substituted-pyrrol-1-yl)-alkyl)pyran-2-ones and derivativesthereof as disclosed in U.S. Pat. No. 4,647,576, Searle's SC-45355 (a3-substituted pentanedioic acid derivative) dichloroacetate, imidazoleanalogs of mevalonolactone as disclosed in PCT application WO 86/07054,3-carboxy-2-hydroxy-propane-phosphonic acid derivatives as disclosed inFrench Patent No. 2,596,393, 2,3-disubstituted pyrrole, furan andthiophene derivatives as disclosed in European Patent Application No.0221025, naphthyl analogs of mevalonolactone as disclosed in U.S. Pat.No. 4,686,237, octahydronaphthalenes such as disclosed in U.S. Pat. No.4,499,289, keto analogs of mevinolin (lovastatin) as disclosed inEuropean Patent Application No.0,142,146 A2, and quinoline and pyridinederivatives disclosed in U.S. Pat. No. 5,506,219 and 5,691,322.

[0119] In addition, phosphinic acid compounds useful in inhibiting HMGCoA reductase suitable for use herein are disclosed in GB 2205837.

[0120] The squalene synthetase inhibitors suitable for use hereininclude, but are not limited to, α-phosphono-sulfonates disclosed inU.S. Pat. No. 5,712,396, those disclosed by Biller et al, J. Med. Chem.,1988, Vol. 31, No. 10, pp 1869-1871, including isoprenoid(phosphinyl-methyl)phosphonates as well as other known squalenesynthetase inhibitors, for example, as disclosed in U.S. Pat. No.4,871,721 and 4,924,024 and in Biller, S. A., Neuenschwander, K.,Ponpipom, M. M., and Poulter, C. D., Current Pharmaceutical Design, 2,1-40 (1996).

[0121] In addition, other squalene synthetase inhibitors suitable foruse herein include the terpenoid pyrophosphates disclosed by P. Ortiz deMontellano et al, J. Med. Chem., 1977, 20, 243-249, the farnesyldiphosphate analog A and presqualene pyrophosphate (PSQ-PP) analogs asdisclosed by Corey and Volante, J. Am. Chem. Soc., 1976, 98, 1291-1293,phosphinylphosphonates reported by McClard, R. W. et al, J.A.C.S., 1987,109, 5544 and cyclopropanes reported by Capson, T. L., PhD dissertation,June, 1987, Dept. Med. Chem. U of Utah, Abstract, Table of Contents, pp16, 17, 40-43, 48-51, Summary.

[0122] Other hypolipidemic agents suitable for use herein include, butare not limited to, fibric acid derivatives, such as fenofibrate,gemfibrozil, clofibrate, bezafibrate, ciprofibrate, clinofibrate and thelike, probucol, and related compounds as disclosed in U.S. Pat. No.3,674,836, probucol and gemfibrozil being preferred, bile acidsequestrants such as cholestyramine, colestipol and DEAE-Sephadex(Secholex®, Policexide®), as well as lipostabil (Rhone-Poulenc), EisaiE-5050 (an N-substituted ethanolamine derivative), imanixil (HOE-402),tetrahydrolipstatin (THL), istigmastanylphosphorylcholine (SPC, Roche),aminocyclodextrin (Tanabe Seiyoku), Ajinomoto AJ-814 (azulenederivative), melinamide (Sumitomo), Sandoz 58-035, American CyanamidCL-277,082 and CL-283,546 (disubstituted urea derivatives), nicotinicacid, acipimox, acifran, neomycin, p-aminosalicylic acid, aspirin,poly(diallylmethylamine) derivatives such as disclosed in U.S. Pat. No.4,759,923, quaternary amine poly(diallyldimethylammonium chloride) andionenes such as disclosed in U.S. Pat. No. 4,027,009, and other knownserum cholesterol lowering agents.

[0123] The other hypolipidemic agent may be an ACAT inhibitor such asdisclosed in, Drugs of the Future 24, 9-15 (1999), (Avasimibe); “TheACAT inhibitor, Cl-1011 is effective in the prevention and regression ofaortic fatty streak area in hamsters”, Nicolosi et al, Atherosclerosis(Shannon, Irel). (1998), 137(1), 77-85; “The pharmacological profile ofFCE 27677: a novel ACAT inhibitor with potent hypolipidemic activitymediated by selective suppression of the hepatic secretion ofApoB100-containing lipoprotein”, Ghiselli, Giancarlo, Cardiovasc. DrugRev. (1998), 16(1), 16-30; “RP 73163: a bioavailablealkylsulfinyl-diphenylimidazole ACAT inhibitor”, Smith, C., et al,Bioorg. Med. Chem. Lett. (1996), 6(1), 47-50; “ACAT inhibitors:physiologic mechanisms for hypolipidemic and anti-atheroscleroticactivities in experimental animals”, Krause et al, Editor(s): Ruffolo,Robert R., Jr.; Hollinger, Mannfred A., Inflammation: Mediators Pathways(1995), 173-98, Publisher: CRC, Boca Raton, Fla.; “ACAT inhibitors:potential anti-atherosclerotic agents”, Sliskovic et al, Curr. Med.Chem. (1994), 1(3), 204-25; “Inhibitors of acyl-CoA:cholesterol O-acyltransferase (ACAT) as hypocholesterolemic agents. 6. The firstwater-soluble ACAT inhibitor with lipid-regulating activity. Inhibitorsof acyl-CoA:cholesterol acyltransferase (ACAT). 7. Development of aseries of substituted N-phenyl-N′-[(1-phenylcyclopentyl)methyl]ureaswith enhanced hypocholesterolemic activity”, Stout et al, Chemtracts:Org. Chem. (1995), 8(6), 359-62, or TS-962 (Taisho Pharmaceutical Co.Ltd).

[0124] The hypolipidemic agent may be an upregulator of LD2 receptoractivity such as MD-700 (Taisho Pharmaceutical Co. Ltd) and LY295427(Eli Lilly).

[0125] The hypolipidemic agent may be a cholesterol absorption inhibitorpreferably Schering-Plough's SCH48461 as well as those disclosed inAtherosclerosis 115, 45-63 (1995) and J. Med. Chem. 41, 973 (1998).

[0126] The hypolipidemic agent may be an ileal Na⁺/bile acidcotransporter inhibitor such as disclosed in Drugs of the Future, 24,425-430 (1999).

[0127] Preferred hypolipidemic agents are pravastatin, lovastatin,simvastatin, atorvastatin, fluvastatin, cerivastatin, atavastatin andZD-4522.

[0128] The above-mentioned U.S. patents are incorporated herein byreference. The amounts and dosages employed will be as indicated in thePhysician's Desk Reference and/or in the patents set out above.

[0129] The compounds of formula I of the invention will be employed in aweight ratio to the hypolipidemic agent (were present), within the rangefrom about 500:1 to about 1:500, preferably from about 100:1 to about1:100.

[0130] The dose administered must be carefully adjusted according toage, weight and condition of the patient, as well as the route ofadministration, dosage form and regimen and the desired result.

[0131] The dosages and formulations for the hypolipidemic agent will beas disclosed in the various patents and applications discussed above.

[0132] The dosages and formulations for the other hypolipidemic agent tobe employed, where applicable, will be as set out in the latest editionof the Physicians' Desk Reference.

[0133] For oral administration, a satisfactory result may be obtainedemploying the MTP inhibitor in an amount within the range of from about0.01 mg/kg to about 500 mg and preferably from about 0.1 mg to about 100mg, one to four times daily.

[0134] A preferred oral dosage form, such as tablets or capsules, willcontain the MTP inhibitor in an amount of from about 1 to about 500 mg,preferably from about 2 to about 400 mg, and more preferably from about5 to about 250 mg, one to four times daily.

[0135] For oral administration, a satisfactory result may be obtainedemploying an HMG CoA reductase inhibitor, for example, pravastatin,lovastatin, simvastatin, atorvastatin, fluvastatin or cerivastatin indosages employed as indicated in the Physician's Desk Reference, such asin an amount within the range of from about 1 to 2000 mg, and preferablyfrom about 4 to about 200 mg.

[0136] The squalene synthetase inhibitor may be employed in dosages inan amount within the range of from about 10 mg to about 2000 mg andpreferably from about 25 mg to about 200 mg.

[0137] A preferred oral dosage form, such as tablets or capsules, willcontain the HMG CoA reductase inhibitor in an amount from about 0.1 toabout 100 mg, preferably from about 5 to about 80 mg, and morepreferably from about 10 to about 40 mg.

[0138] A preferred oral dosage form, such as tablets or capsules willcontain the squalene synthetase inhibitor in an amount of from about 10to about 500 mg, preferably from about 25 to about 200 mg.

[0139] The other hypolipidemic agent may also be a lipoxygenaseinhibitor including a 15-lipoxygenase (15-LO) inhibitor such asbenzimidazole derivatives as disclosed in WO 97/12615, 15-LO inhibitorsas disclosed in WO 97/12613, isothiazolones as disclosed in WO 96/38144,and 15-LO inhibitors as disclosed by Sendobry et al “Attenuation ofdiet-induced atherosclerosis in rabbits with a highly selective15-lipoxygenase inhibitor lacking significant antioxidant properties,Brit. J. Pharmacology (1997) 120, 1199-1206, and Cornicelli et al,“15-Lipoxygenase and its Inhibition: A Novel Therapeutic Target forVascular Disease”, Current Pharmaceutical Design, 1999, 5, 11-20.

[0140] The compounds of formula I and the hypolipidemic agent may beemployed together in the same oral dosage form or in separate oraldosage forms taken at the same time.

[0141] The compositions described above may be administered in thedosage forms as described above in single or divided doses of one tofour times daily. It may be advisable to start a patient on a low dosecombination and work up gradually to a high dose combination.

[0142] The preferred hypolipidemic agent is pravastatin, simvastatin,lovastatin, atorvastatin, fluvastatin or cerivastatin.

[0143] The other type of therapeutic agent which may be optionallyemployed with the aP2 inhibitor of formula I may be 1, 2, 3 or more ofan anti-obesity agent including a beta 3 adrenergic agonist, a lipaseinhibitor, a serotonin (and dopamine) reuptake inhibitor, a thyroidreceptor beta drug and/or an anorectic agent.

[0144] The beta 3 adrenergic agonist which may be optionally employed incombination with a compound of formula I may be AJ9677(Takeda/Dainippon), L750355 (Merck), or CP331648 (Pfizer) or other knownbeta 3 agonists as disclosed in U.S. Pat. Nos. 5,541,204, 5,770,615,5,491,134, 5,776,983 and 5,488,064, with AJ9677, L750,355 and CP331648being preferred.

[0145] The lipase inhibitor which may be optionally employed incombination with a compound of formula I may be orlistat or ATL-962(Alizyme), with orlistat being preferred.

[0146] The serotonin (and dopoamine) reuptake inhibitor which may beoptionally employed in combination with a compound of formula I may besibutramine, topiramate (Johnson & Johnson) or axokine (Regeneron), withsibutramine and topiramate being preferred.

[0147] The thyroid receptor beta compound which may be optionallyemployed in combination with a compound of formula I may be a thyroidreceptor ligand as disclosed in WO97/21993 (U. Cal SF), WO99/00353(KaroBio) and GB98/284425 (KaroBio), with compounds of the KaroBioapplications being preferred.

[0148] The anorectic agent which may be optionally employed incombination with a compound of formula I may be dexamphetamine,phentermine, phenylpropanolamine or mazindol, with dexamphetamine beingpreferred.

[0149] The various anti-obesity agents described above may be employedin the same dosage form with the compound of formula I or in differentdosage forms, in dosages and regimens as generally known in the art orin the PDR.

[0150] The other type of therapeutic agent which may be optionallyemployed with the aP2 inhibitor of formula I may be 1, 2, 3 or more ofan antihypertensive agent including an ACE inhibitor, a vasopeptidaseinhibitor, an angiotensin II antagonist, a calcium channel blocker, apotassium channel opener, an alpha-blocker, a beta blocker, a centrallyacting alpha agonist, and/or a diuretic.

[0151] The ACE inhibitor which may be optionally employed in combinationwith a compound of formula I may be lisinopril, enalapril, quinapril,benazepril, fosinopril, fentiapril, ramipril, captopril, enalaprilat,moexipril, tranolapril, perindopril, ceranopril, zofenopril or cetapril.

[0152] Preferred ACE inhibitors are captopril, as well as fosinopril,enalapril, lisinopril, quinapril, benazepril, fentiapril, ramipril, andmoexipril.

[0153] The vasopeptidase inhibitor (also known as NEP/ACE inhibitors)which may be optionally employed with the aP2 inhibitor of formula I maybe omapatrilat (most preferred) and[S-(R*,R*)]-hexahydro-6-[(2-mercapto-1-oxo-3-phenylpropyl)amino]-2,2-dimethyl-7-oxo-1H-azepine-1-aceticacid (BMS 189,921 also preferred), as well as those disclosed in U.S.Pat. Nos. 5,362,727, 5,366,973, 5,225,401, 4,722,810, 5,223,516,4,749,688. U.S. Pat. No. 5,504,080, U.S. Pat. No. 5,552,397, U.S. Pat.No. 5,612,359, U.S. Pat. No. 5,525,723, European Patent Application0599,444, 0481,522, 0599,444, 0595,610, European Patent Application0534363.A2, 534,396 and 534,492, and European Patent Application0629627.A2.

[0154] Preferred are those NEP/ACE inhibitors which are designated aspreferred in the above patents/applications which U.S.patents/applications are incorporated herein by reference.

[0155] The angiotensin II receptor antagonist (also referred to hereinas angiotensin II antagonist or AII antagonist) which may be optionallyemployed in combination with a compound of formula I may be irbesartan,losartan, valsartan, candesartan, telmisartan, tasosartan and/oreprosartan, with irbesartan or losartan being preferred.

[0156] The calcium channel blocker (also referred to as a calciumantagonist) which may be optionally employed in combination with acompound of formula I may be amlodipine, diltiazem, nifedipine,verapamil, feldodipine, nisoldipine, isradipine and/or nicardipine, withamlodipine, diltiazem, verapamil and nifedipine being preferred.

[0157] The alpha-blocker which may be optionally employed in combinationwith a compound of formula I may be terazosin, doxazosin or prazosin,all of which are preferred.

[0158] The beta-blocker which may be optionally employed in combinationwith a compound of formula I may be nadolol, atenolol, propranolol,metoprolol, carvediol or sotalol, with atenolol and nadolol beingpreferred.

[0159] The potassium channel opener which may be optionally employed incombination with a compound of formula I may be minoxidil.

[0160] The centrally acting α agonist antihypertensive agent which maybe optionally employed in combination with a compound of formula I maybe clonidine or guanfacine, with clonidine being preferred.

[0161] The diuretic which may be optionally employed in connection witha compound of formula I may be hydrochlorothiazide, torasemide,furosemide, spironolactone and/or indapamide, with hydrochlorothiazideand furosemide being preferred.

[0162] The antiplatelet agent (also known as platelet aggregationinhibitor) which may be optionally employed in combination with acompound of formula I may be aspirin, clopidogrel, ticlopidine,dipyridamole, abciximab, tirofiban, eptifibatide, anagrelide and/orifetroban, with aspirin and clopidogrel being preferred.

[0163] The anti-infective agent which may be optionally employed incombination with a compound of formula I may be an anti-infective thatis effective against chlamydial infections, such as azithromycin,gatifloxacin, ciprofloxacin, levofloxacin and trovafloxacin, withazithromycin and gatifloxacin being preferred.

[0164] The various antihypertensive agents and antiplatelet agents andanti-infective agents described above may be employed in the same dosageform with the compound of formula I or in different dosage forms, indosages and regimens as generally known in the art or in the PDR.

[0165] In carrying our the method of the invention, a pharmaceuticalcomposition will be employed containing the compounds of structure I,with or without another therapeutic agent, in association with apharmaceutical vehicle or diluent. The pharmaceutical composition can beformulated employing conventional solid or liquid vehicles or diluentsand pharmaceutical additives of a type appropriate to the mode ofdesired administration. The compounds can be administered to mammalianspecies including humans, monkeys, dogs, etc. by an oral route, forexample, in the form of tablets, capsules, granules or powders, or theycan be administered by a parenteral route in the form of injectablepreparations. The dose for adults is preferably between 20 and 2,000 mgper day, which can be administered in a single dose or in the form ofindividual doses from 1-4 times per day.

[0166] A typical capsule for oral administration contains compounds ofstructure I (250 mg), lactose (75 mg) and magnesium stearate (15 mg).The mixture is passed through a 60 mesh sieve and packed into a No. 1gelatin capsule.

[0167] A typical injectable preparation is produced by asepticallyplacing 250 mg of compounds of structure I into a vial, asepticallyfreeze-drying and sealing. For use, the contents of the vial are mixedwith 2 mL of physiological saline, to produce an injectable preparation.

[0168] aP2 inhibitor activity of the compounds of the invention may bedetermined by use of an in vitro assay system which measures thepotentiation of inhibition of aP2 by displacement of a fluorescentsubstrate from aP2 by the inhibitor. Inhibition constants (Ki values)for the aP2 inhibitors of the invention may be determined by the methoddescribed below:

[0169] Production of Purified Recombinant Human aP2 Protein. Recombinanthuman aP2 protein is produced by standard recombinant DNA technology. Inthe typical case, aP2 is produced by heterologous expression in E. colistrain BL21(D53) transformed with pET11a vector containing the fulllength human aP2 cDNA (Baxa, C. A., Sha, R. S., Buelt, M. K., Smith, A.J., Matarese, V., Chinander, L. L., Boundy, K. L., and Bernlohr, D. A.(1989). Human adipocyte lipid-binding protein: purification of theprotein and cloning of its complementary DNA. Biochemistry 28: 8683-8690and Xu, Z., Buelt, M. K., Banaszak, L. J., and Bernlohr, D. A. (1991).Expression, purification and crystallization of the adipocyte lipidbinding protein. J. Biol. Chem. 266: 14367-14370). Purification of aP2from E. coli is conducted as described by Xu, yielding essentiallyhomogeneous aP2 protein with molecular weight 14600 daltons and free ofendogenous fatty acids. The purified aP2 is capable of binding up to onemole of free fatty acid per mole protein. The binding and structuralproperties of recombinant aP2 protein were previously shown to beidentical to aP2 protein isolated from adipose tissue.

[0170] In vitro assay of aP2 inhibitors. Inhibitors of aP2 are evaluatedin a homogeneous fluorescent-based competition assay using recombinantaP2 protein and 1,8-anilino-naphthalene-sulfonic acid (1,8-ANS) as assaysubstrate. This competition assay was adapted from generalizedprocedures described previously (Kane, C. D. and Bernlohr, D. A. (1996).A simple assay for intracellular lipid-binding proteins usingdisplacement of 1-anilino-8-sulfonic acid. (1996) Anal. Biochem. 233:197-204 and Kurian E., Kirk, W. R. and Prendergast, F. G. (1996)Affinity of fatty acid for r-rat intestinal fatty acid binding protein.Biochemistry, 35, 3865-3874). The method relies on the increase influorescence quantum yield of 1,8-ANS upon binding to the fatty acidbinding site of aP2. The assay is run using appropriate concentrationsof inhibitor, 1,8-ANS, and aP2 protein, in order to calculate theinhibitor binding constant (Ki) for compounds being evaluated. The Kicalculation was based on the procedure previously described forcalculation of dissociation constants described by Kurian. Lower Kivalues indicate higher affinities of compounds binding to aP2.

[0171] In the assay as conducted for the inhibitors described herein, aseries of aliquots of aP2 (5 μM) in solution in 10 mM potassiumphosphate buffer (pH 7.0) are mixed with an equimolar concentration oftest compound, followed by the addition of a series of increasingconcentrations of 1,8-ANS (from 0 to 5 μM). The assay typically isconducted in 96-well plate format with reagents added using roboticinstrumentation (Packard Multiprobe 104). The fluorescence value foreach test is determined using a Cytofluor-4000 multi-well fluorescenceplate reader (Perceptive Biosystems) using excitation wavelength 360 nmand emission wavelength 460 nm, or using other suitablespectrofluorometer. In preparation for the assay, test compounds areinitially prepared at 10 mM in dimethylsulfoxide. All subsequentdilutions and assay additions are made in 10 mM potassium phosphatebuffer, pH 7.0.

[0172] X-ray crystallography of the inhibitor-aP2 complex can beperformed by one skilled in the art using contemporary biophysicalmethodologies and commercial instrumentation. Such crystallographic datacan be used to conclusively determine if a compound used in the presentinvention has embodied the structural requirement necessary forinhibition of aP2. An example of such an X-ray crystallographicdetermination is presented below:

[0173] Crystals of aP2 complexed with the inhibitors were typicallygrown by the hanging drop method. aP2, at 8.3 mg/ml, waspre-equilibrated with 1-5 mM of the inhibitor in 0.1 M Tris-HCl pH 8.0,1% w/v DMSO for four hours. 2 μl drops containing equilibrated proteinand reservoir solution at a 1:1 ratio were suspended on plastic coverslips and equilibrated against a 1 ml reservoir containing 2.6-3.0 Mammonium sulfate in 0.1 M Tris-HCl pH 8.0. Crystals typically appearedin 2-3 days and reached maximum size within 2 weeks. Data was typicallycollected on a single flash-frozen crystal (Oxford Cryosystems) using aRigaku rotating anode and an R-axis II image plate detector of a Brukermultiwire area detector. Diffraction from aP2 crystals was excellent.Diffraction was consistently observed to better than 2.0 A resolutionoften to beyond 1.5 Å resolution. Data was processed either withDENZO/SCALEPACK (R-axis II data), or Xengen (Bruker data). XPLOR wasused for structure refinement and model building was done using themolecular modeling package CHAIN. After a single round of refinement,examination of the F_(o)-F_(c) map typically allowed facile building ofthe inhibitor into aP2 binding cavity. Iterative fitting and refinementwere continued until improvement was no longer seen in the electrondensity map or R-free.

[0174] The following working Examples represent preferred embodiments ofthe invention.

EXAMPLE 1

[0175]

[0176] A solution of 2-bromo-benzoic acid (21.8 g, 108 mmol), 4-dimethylamino pyridine (1 g, 8.19 mmol),1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (22.6 g, 118mmol) and benzoin (20 g, 94.2 mmol) in dichloromethane (200 mL) wasstirred at room temperature for 4 hr. The reaction mixture was washedwith water (2×50 mL), brine (50 mL), dried over anhydrous MgSO₄ andconcentrated to give the ketoester as a colorless oil (36 g).

[0177] A mixture of ketoester (36 g, 94.2 mmol) and ammonium acetate (36g, 471 mmol) in glacial acetic acid (350 mL) was stirred at reflux for1.5 hr. The reaction mixture was cooled, diluted with water, andextracted with ethyl acetate (3×300 mL). The combined organic layerswere washed with water (2×100 mL), saturated aqueous sodium bicarbonatesolution (2×100 mL), and brine (100 mL), dried over anhydrous MgSO₄ andconcentrated to get yellow-orange oil. The crude product wasrecrystallized from hot methanol to get the title compound as off-whitesolid (21.6 g, 61%).

[0178] Nitrogen was bubbled through a solution of Part A compound (1.48g, 3.93 mmol), 3-formyl phenyl boronic acid (766 mg, 5.11 mmol) andaqueous sodium carbonate (3.2 mL, 2M, 6.4 mmol) in toluene (10 mL) andethanol (4.2 mL) at room temperature for 30 min.Tetrakis(triphenylphosphine) palladium(0) (150 mg, 0.13 mmol) was addedand the mixture was stirred at 80° C. for 14 hr under argon. Thereaction mixture was cooled to room temperature and extracted with ethylacetate. The combined organic extracts were washed with brine, driedover anhydrous MgSO₄ and concentrated. The crude product was purified byflash chromatography on silica gel, eluting with a step gradient of 1:9to 2:8 ethyl acetate/hexane to give title compound as a colorless oil(800 mg, 51%).

[0179] Sodium borohydride (19 mg, 0.5 mmol) was added slowly to asolution of Part B compound (494 mg, 1.23 mmol) in anhydrous methanol (2mL) at 0° C. The reaction was stirred for 2 hr at 0° C., and then warmedto room temperature. The pH was adjusted to 2 with conc. HCl andconcentrated. The residue was partitioned between ethyl acetate andwater. The organic layer was washed with water, dried (MgSO₄) andconcentrated to give the title compound as a white foam (360 mg, 89%).

[0180] To a stirred solution of Part C compound (7.5 g, 18.6 mmol) indioxane (62 mL) at room temperature was added zinc chloride (78 mg, 0.54mmol) followed by thionyl chloride (2.74 mL, 37.5 mmol). The reactionwas stirred for 1 hr and concentrated. The residue was dissolved inethyl acetate, washed with brine, dried over anhydrous MgSO₄ andconcentrated to give the title compound as a viscous oil (8.0 g, 100%).

[0181] A solution of Part D compound (8.0 g, 18.6 mmol) and sodiumcyanide (1.39 g, 28.2 mmol) in acetonitrile (75 mL) and water (7 mL) wasstirred at reflux for 14 hr. The reaction mixture was cooled to roomtemperature, concentrated. The residue was partitioned betweendichloromethane and water. The organic layer was dried (MgSO₄) andconcentrated. The crude product was purified by flash chromatography onsilica gel, eluting with a step gradient of 5:95 to 15:85 ethylacetate/hexane to give title compound as a white solid (6.4 g, 83.6%).

[0182] A solution of Part E compound (6.18 g, 15.0 mmol) andazidotrimethyltin (4.32 g, 21.0 mmol) in xylene (50 mL) was refluxed for18 hr. The reaction mixture was cooled to room temperature, methanol(150 mL) was added and the mixture was stirred for 30 min andconcentrated. The crude product was purified by flash chromatography onsilica gel, eluting with a step gradient of 3:7 to 5:5 ethylacetate/hexane and then with 95:5 dichloromethane/methanol to give titlecompound as a white solid (5.96 g, 87%). The compound can berecrystallized from hot ethanol.

EXAMPLE 2

[0183]

[0184] Example 1 Part B compound (401 mg, 1 mmol) was added to asolution of silicon tetrachloride (170 mg, 115 μL, 1 mmol) and sodiumazide (195 mg, 3 mmol) in anhydrous acetonitrile (3 mL) at 0° C. Thereaction mixture was warmed to room temperature, then to 50° C. andstirred for 24 hr. The reaction was cooled to room temperature andpoured into aqueous saturated sodium carbonate solution. The pH of themixture was adjusted between 9-10 with sodium carbonate solution and itwas extracted with chloroform (3×10 mL). The combined organic layerswere washed with water, dried over anhydrous MgSO₄ and concentrated. Thecrude product was purified by flash chromatography on silica gel,eluting with a step gradient of 3:97 to 5:95 ethyl acetate/hexane togive title compound as a colorless oil (200 mg, 50%).

[0185] A solution of Part A compound (199 mg, 0.5 mmol) andazidotrimethyltin (145 mg, 0.7 mmol) in xylene (5 mL) was heated at 100°C. for 18 hr. The reaction mixture was cooled to room temperature,methanol (8 mL) was added, stirred for 30 min, filtered andconcentrated. Flash chromatography on silica gel, eluting with 1:4 ethylacetate/hexane and then with 95:5:0.15 dichloromethane/methanol/aceticacid gave impure product. Furthur purification by flash chromatographyon silica gel, eluting with a step gradient of 1:4 to 1:1 ethylacetate/hexane and then with 95:5 to 90:10 dichloromethane/methanol gavethe title compound as a foam (70 mg, 32%).

EXAMPLE 3

[0186]

[0187] Nitrogen was bubbled through a solution of Example 1 Part Acompound (5 g, 13.29 mmol), 3-amino phenyl boronic acid (2.37 g, 17.29mmol) and sodium carbonate (11 mL, 2M, 22 mmol) in toluene (40 mL) andethanol (15 mL) at room temperature for 30 min.Tetrakis(triphenylphosphine)-palladium(0) (508 mg, 0.43 mmol) was addedand the reaction mixture was heated at 80° C. for 18 hr. The reactionmixture was cooled to room temperature and partitioned between diethylether and water. The organic layer was washed with water, brine, driedover anhydrous MgSO₄ and concentrated. The crude product was purified byflash chromatography eluting with 1:3 ethyl acetate/hexane to give titlecompound as a pale yellow foam (2.56 g, 49%).

[0188] To a slurry of Part A compound (2.56 g, 6.60 mmol) and potassiumcarbonate (918 mg, 6.60 mmol) in anhydrous dimethyl formamide (20 mL)was added tert-butyl bromoacetate (975 μL, 6.60 mmol). The reactionmixture was stirred at room temperature for 18 hr. Additional tert-butylbromoacetate (150 μL, 1.01 mmol) was added and the mixture was stirredfor 7 hr. The reaction was partitioned between diethyl ether and aqueoussodium bicarbonate solution. The organic layer was washed with water,and brine, then dried over anhydrous MgSO₄ and concentrated. The crudeproduct was purified by flash chromatography eluting with 15:85 ethylacetate/hexane to give title compound as a foam (2.230 g, 67%).

[0189] A solution of Part B compound (2.230 g, 4.4 mmol) intrifluoroacetic acid (15 mL) and dichloromethane (40 mL) was stirred atroom temperature for 18 hr. The reaction mixture was concentrated, theresidue was partitioned between ethyl acetate and water. The aqueouslayer was basified with 1N NaOH and then the pH was adjusted between 3-4with 10% citric acid solution. The organic layer was separated andwashed with water and brine, dried over anhydrous MgSO₄ andconcentrated. The crude product was purified by flash chromatographyeluting with 7:93 methanol/dichloromethane to give an oily foam whichwas triturated from ethyl acetate/hexane to get the title compound as ayellow foam (1.692 g, 86%).

EXAMPLE 4

[0190]

[0191] To a solution of Example 3 Part A compound (149 mg, 0.38 mmol) indichloromethane (2 mL) was added diisopropylethylamine (100 μL),followed by ethyl oxalyl chloride (147 μL, 0.42 mmol). The reaction wasstirred for 2 hr, partitioned between ethyl acetate and aqueous HCl(1N). The organic layer was washed with water, saturated sodiumbicarbonate solution, and brine, dried over anhydrous MgSO₄ andconcentrated to get the crude ester as a yellow-brown foam (189 mg). Toa solution of the crude ester in methanol (3 mL) was added dropwiseaqueous NaOH (˜800 μL, 1N) until the solution became turbid. Precipitatewas formed after stirring the solution overnight. The reaction waspartitioned between ethyl acetate and aqueous HCl (1N). The organiclayer was washed with water, and brine, dried over anhydrous MgSO₄ andconcentrated. The crude product was triturated with ethyl acetate andhexane to give the title compound as an off-white solid (118 mg, 67%).

EXAMPLE 5

[0192]

[0193] A mixture of benzil (10 g, 47.6 mmol) and ammonium acetate (44 g,564 mmol) in glacial acetic acid (260 mL) was treated with2-bromobenzaldehyde (5.5 mL, 47.6 mmol) and stirred at 105° C. for 3 hr.The reaction mixture was cooled, diluted with water, and the precipitatewas filtered. The solid was dissolved in warm ethyl acetate. The organiclayer was washed with water, and brine, dried over anhydrous MgSO₄ andconcentrated. The crude product was triturated from ethyl acetate/hexaneto give the title compound as an off-white solid (16.55 g, 93%).

[0194] To a solution of Part A compound (2.5 g, 6.67 mmol) and ethyliodide (1.15 g, 7.3 mmol) in anhydrous dimethylformamide (17 mL) wasadded potassium carbonate (922 mg, 6.67 mmol). The reaction mixture wasstirred at room temperature overnight, partitioned between ethylacetate/water. The organic layer was washed with water, dried overanhydrous MgSO₄ and concentrated to give the title compound as asemi-solid (2.5 g, 94%).

[0195] Nitrogen was bubbled through a solution of Part B compound (2.0g, 4.96 mmol), 3-formyl phenyl boronic acid (966 mg, 6.44 mmol) andaqueous sodium carbonate (4 mL, 2M, 8 mmol) in toluene (15 mL) andethanol (8 mL) at room temperature for 30 min.Tetrakis(triphenylphosphine) palladium(0) (190 mg, 0.16 mmol) was addedand the mixture was stirred at 80° C. for 36 hr under argon. Thereaction mixture was cooled to room temperature and extracted with ethylacetate. The combined organic extracts were washed with brine, driedover anhydrous MGSO₄ and concentrated. The crude product was purified byflash chromatography on silica gel, eluting with a step gradient of 1:9to 2:8 ethyl acetate/hexane to give title compound as an oil (1.7 g,80%).

[0196] Sodium borohydride (57 mg, 1.51 mmol) was added slowly to asolution of Part C compound (900 mg, 2.1 mmol) in anhydrous methanol (5mL) at 0° C. The reaction was stirred for 2 hr at 0° C. Additionalsodium borohydride (57 mg, 1.51 mmol) was added and stirring wascontinued for 2 hr and then the reaction mixture was warmed to roomtemperature. The mixture was partitioned between ethylacetate/chloroform and water. The organic layer was washed with water,dried (MgSO₄) and concentrated to give the title compound as a whitefoam (650 mg, 72%).

[0197] To a stirred solution of Part D compound (645 mg, 1.5 mmol) indioxane (8 mL) at room temperature was added zinc chloride (6 mg, 0.045mmol) followed by thionyl chloride (220 μL, 3.0 mmol). The reaction wasstirred for 1 hr and concentrated. The residue was dissolved in ethylacetate, washed with brine and 5% aqueous sodium bicarbonate solution,dried over anhydrous MgSO₄ and concentrated to give the title compoundas a foam (650 mg, 95%).

[0198] A solution of Part E compound (600 mg, 1.34 mmol) and sodiumcyanide (92 mg, 1.88 mmol) in acetonitrile (6 mL) and water (400 μL) wasstirred at reflux overnight. Additional sodium cyanide (92 mg, 1.88mmol) in water (400 μL) was added and the refluxing continued for 6 hr.Additional sodium cyanide (50 mg, 1.01 mmol) in water (400 μL) was addedand refluxing was continued for 2 hr. The reaction mixture was cooled toroom temperature and concentrated. The residue was partitioned betweendichloromethane and water. The organic layer was dried (MgSO₄) andconcentrated. The crude product was purified by flash chromatography onsilica gel, eluting with a step gradient of 10:90 to 30:70 ethylacetate/hexane to give title compound as a white solid (300 mg, 51%).

[0199] A solution of Part F compound (255 mg, 0.58 mmol) andazidotrimethyltin (167 mg, 0.81 mmol) in xylene (2 mL) was heated at130° C. overnight. The reaction mixture was cooled to room temperature,methanol (8 mL) was added and the mixture was stirred for 30 min. Themilky white precipitate was filtered and the filtrate was concentrated.The crude product was purified by flash chromatography on silica gel,eluting with a step gradient of 1:1 ethyl acetate/hexane and then with95:5 dichloromethane/methanol to give title compound as a white foam(216 mg, 77%).

EXAMPLE 6

[0200]

[0201] Nitrogen was bubbled through a solution of Example 5 Part Bcompound (1.0 g, 4.96 mmol), 3-aminophenyl boronic acid (442 mg, 3.22mmol) and aqueous sodium carbonate (2 mL, 2M, 4 mmol) in toluene (7 mL)and ethanol (4 mL) at room temperature for 30 min.Tetrakis(triphenylphosphine) palladium(0) (95 mg, 0.08 mmol) was addedand the mixture was stirred at 80° C. overnight under argon. Thereaction mixture was cooled to room temperature and extracted with ethylacetate. The combined organic extracts were washed with brine, driedover anhydrous MgSO₄ and concentrated. The crude product was purified byflash chromatography on silica gel, eluting with a step gradient of 2:8to 3:7 ethyl acetate/hexane to give title compound as a white solid (400mg, 39%).

[0202] The mixture of Part A compound (400 mg, 0.96 mmol),diisopropylethylamine (333 μL, 1.92 mmol), and ethylbromoacetate (95 μL,0.86 mmol) in anhydrous dimethylformamide (3 mL) was stirred at roomtemperature overnight. The reaction mixture was partitioned betweenethyl acetate and water. The organic layer was washed with water, brine,dried over anhydrous MgSO₄ and concentrated. The crude product waspurified by flash chromatography on silica gel, eluting with a stepgradient of 2:8 to 3:7 ethyl acetate/hexane to give title compound as afoam (400 mg, 83%).

[0203] A solution of Part B compound (400 mg, 0.77 mmol) in aqueoussodium hydroxide (2.3 mL, 1N, 2.3 mmol) and methanol (15 mL) was stirredat room temperature for 2 hr. The reaction mixture was concentrated to awhite suspension in water bath at 30° C. The suspension was dissolved indistilled water. The pH was adjusted to 4 by aqueous citric acid (1N).The white precipitate was dissolved in ethyl acetate. The organic layerwas washed with water, brine, dried over anhydrous MgSO₄ andconcentrated to give the title compound as a foam (350 mg, 96%).

EXAMPLE 7

[0204]

[0205] Example 5 Part C compound (214 mg, 0.5 mmol) was added to asolution of silicon tetrachloride (58 μL, 0.5 mmol) and sodium azide (98mg, 1.5 mmol) in anhydrous acetonitrile (3 mL) at 0° C. The reactionmixture was warmed to room temperature, then to 50° C. and stirred for48 hr. The reaction was cooled to room temperature and poured intoaqueous saturated sodium carbonate solution. The pH of the mixture wasadjusted between 9-10 with sodium carbonate solution and it wasextracted with chloroform twice. The combined organic layers were washedwith water, dried over anhydrous MGSO₄ and concentrated. The crudeproduct was purified by flash chromatography on silica gel, eluting witha step gradient of 15:85 to 20:80 ethyl acetate/hexane to give titlecompound as a foam (56 mg, 26%).

[0206] A solution of Part A compound (50 mg, 0.11 mmol) andazidotrimethyltin (34 mg, 0.16 mmol) in xylene (3 mL) was heated at 100°C. for 48 hr. The reaction mixture was concentrated to remove allxylene. Fresh xylene (250 μL) and azidotrimethyltin (34 mg, 0.16 mmol)was added and the mixture was heated at 130° C. overnight. The reactionmixture was cooled to room temperature, methanol (8 mL) was added,stirred for 30 min, filtered and concentrated. Flash chromatography onsilica gel, eluting with a step gradient of 1:4 to 1:1 ethylacetate/hexane and then with 95:5 to 90:10 dichloromethane/methanol gavethe title compound as a foam (45 mg, 87%).

EXAMPLE 8

[0207]

[0208] Nitrogen was bubbled through a solution of Example 5 Part Bcompound (4.925 g, 17.2 mmol), 3-methoxy phenyl boronic acid (3.50 g,23.0 mmol) and 2M aqueous sodium carbonate (14 mL) in toluene (50 mL)and absolute ethanol (20 mL) at room temperature for 30 min.Tetrakis(triphenylphosphine) palladium(0) (795 mg, 0.68 mmol) was addedand the mixture was stirred at 80° C. for 18 hr under argon. Thereaction mixture was cooled to room temperature and partitioned betweenethyl acetate/diethyl ether and water. The organic layer was washed withbrine, dried over anhydrous MgSO₄ and concentrated. The crude productwas purified by flash chromatography on silica gel, eluting with 1:3ethyl acetate/hexane to give title compound as a light yellow foam (7.34g, 99%).

[0209] To a solution of Part A compound (7.341 g, 17.07 mmol) inanhydrous dichloromethane (100 mL) at 0° C. was added boron tribromidein dichloromethane (38 mL, 1M, 38 mmol). The reaction was stirred for1.5 hr, quenched with aqueous sodium bicarbonate solution and extractedwith ethyl acetate. The organic layer was washed with water, and brine,then dried over anhydrous MgSO₄, filtered quickly and concentrated. Thesolid was triturated with ether/ethyl acetate/methanol to give the titlecompound as a white solid (3.156 g, 91% purity). The mother liquor wasconcentrated and purified by flash chromatography on silica gel, elutingwith 15:85 ethyl acetate/hexane to give title compound which wastriturated from ether/dichloromethane to give a white solid (626mg, >95% purity).

[0210] A slurry of Part B compound (91% pure, 3.15 g) in anhydrousdimethylformamide (35 mL) was warmed to partially dissolve the phenol.The mixture was cooled to 30° C. and potassium carbonate (920 mg, 6.6mmol) was added followed by ethyl bromoacetate (1.35 mL, 12.12 mmol).The reaction mixture was stirred at room temperature for 24 hr.Additional potassium carbonate (920 mg, 6.6 mmol) and ethyl bromoacetate(1.35 mL, 12.12 mmol) was added and stirring was continued for 40 hr.The reaction mixture was partitioned between ethyl acetate and water.The organic layer was washed with water, and brine, then dried overanhydrous MgSO₄ and concentrated. The crude product was purified byflash chromatography on silica gel, eluting with 1:9 ethylacetate/dichloromethane to give title compound as a white foam (2.678 g,77%).

[0211] A solution of Part C (2.670 g, 5.31 mmol) compound in 1,4-dioxane(15 mL) was treated with sodium hydroxide solution (13 mL, 1N, 13 mmol).The reaction mixture was stirred at 50° C. for 45 min. The reactionmixture was cooled to room temperature and acidified with aqueous citricacid solution (25 mL, 10%). The mixture was diluted with water (120 mL)and stirred vigorously for 30 min. The precipitate was filtered, washedwith water and dried to give the title compound as a white solid (2.533g 100%)

EXAMPLE 9

[0212]

[0213] Neat triethyl phosphonate (201 μL, 1.28 mmol) was added dropwiseto a stirred suspension of sodium hydride (52 mg, 1.28 mmol) inanhydrous tetrahydrofuran (2 mL). The mixture was stirred at roomtemperature for 1 hr followed by slow addition of Example 5 Part Ccompound (500 mg, 1.16 mmol) in anhydrous tetrahydrofuran (2 mL). Thereaction mixture stirred for 5 hr. Additional sodium hydride (20 mg,0.50 mmol) was added and stirring was continued for 1 hr. The reactionmixture was partitioned between diethyl ether and water. The organiclayer was washed with water, dried over anhydrous MgSO₄ andconcentrated. The residue was purified by flash chromatography on silicagel, eluting with 3:7 ethyl acetate/hexane to give the Example 9 ethylester (167 mg, 29%).

[0214] A portion of the ester was hydrolyzed during the work up. Theabove aqueous layer was acidified with aqueous citric acid to pH 2. Theseparated solid was extracted with ether. The organic layer was washedwith water, dried over anhydrous MgSO₄ and concentrated. The crudeproduct was purified by flash chromatography on silica gel, eluting witha step gradient of 2:98 to 1:9 methanol/dichloromethane to give titlecompound as a foam (30 mg, 6%). The title compound is also readilyobtained by base hydrolysis of the intermediate ester.

EXAMPLE 10

[0215]

[0216] A solution of Example 5 Part F compound (44 mg, 0.1 mmol) inaqueous sodium hydroxide (250 μL, 10N, 2.5 mmol) and ethanol (2 mL) wasrefluxed for 5 hr and then stirred at room temperature for 14 hr. Thereaction mixture was concentrated and the residue was dissolved inwater. The pH was adjusted to 4 by acetic acid. The precipitate wasfiltered and dissolved in chloroform. The organic solution was washedwith brine, dried over anhydrous MgSO₄ and concentrated. The crudeproduct was purified by flash chromatography on silica gel, eluting witha step gradient of 2:8 ethyl acetate/hexane and then with 95:5 to 90:10dichloromethane/methanol to give title compound as a foam (34 mg, 62%).

EXAMPLE 11

[0217]

[0218] A slurry of the ester described in Example 9 (100 mg, 0.20 mmol)and 10% palladium on carbon (20 mg) in methanol (3 mL) was stirred in aparr shaker under hydrogen (40 psi) for 2 hr. The reaction mixture wasfiltered through a pad of Celite 525 and concentrated to give the titlecompound as a colorless oil (100 mg, 98%).

[0219] A solution of Part A compound (100 mg, 0.2 mmol) in aqueouspotassium hydroxide (600 μL, 2N, 1.2 mmol) and tetrahydrofuran (2 mL)was refluxed for 48 hr. The reaction mixture was concentrated and theresidue was dissolved in water. The pH was adjusted to 2 by aqueousHCl(1N). The white precipitate was extracted into ethyl acetate. Thecombined organic extracts were washed with brine, dried over anhydrousMgSO₄ and concentrated to give a foam. The crude product was purified byflash chromatography on silica gel, eluting with a step gradient of 98:2to 95:5 dichloromethane/methanol to give title compound as a foam (32mg, 34%).

EXAMPLE 12

[0220]

[0221] Nitrogen was bubbled through a solution of Example 1 Part Acompound (10 g, 26.57 mmol), 1-formyl phenyl boronic/acid (5.18 g, 34.55mmol) and aqueous sodium carbonate (21.25 mL, 2M, 42.5 mmol) in toluene(70 mL) and ethanol (27 mL) at room temperature for 30 min. Tetrakis(triphenylphosphine) palladium(0) (1 g, 0.86 mmol) was added and themixture was stirred at 80° C. for 14 hr under argon. The reactionmixture concentrated and diluted with ethyl acetate/water. The aqueouslayer was extracted with ethyl acetate (2×200 mL). The combined organicextracts were washed with brine, dried over anhydrous MgSO₄ andconcentrated. The crude product was purified by flash chromatography onsilica gel, eluting with a step gradient of 1:19 to 2:8 ethylacetate/hexane to give title compound as a yellow solid (6.11 g, 57.3%).Less pure fractions were also collected 2.84 g.

[0222] Part A compound (1 g, 2.49 mmol) was added to a solution ofsilicon tetrachloride (285 μL, 2.49 mmol) and sodium azide (0.486 g,7.47 mmol) in anhydrous acetonitrile (10 mL) at 0° C. The reactionmixture was warmed to room temperature, then to 50° C. and stirred for18 hr. The reaction was cooled to room temperature and poured into amixture of ethyl acetate and aqueous saturated sodium carbonatesolution. The pH of the mixture was adjusted between 9-10 with sodiumcarbonate solution and the aqueous layer was extracted with ethylacetate (3×100 mL). The combined organic layers were washed with brine,dried over anhydrous MgSO₄ and concentrated the title compound as ayellow oil (1.06 g, 107%).

[0223] A solution of Part B compound (0.20 g, 0.50 mmol) andazidotrimethyltin (0.140 g, 0.70 mmol) in p-xylene (2 mL) was refluxedfor 18 hr. The reaction mixture was cooled to room temperature, methanol(10 mL) was added and the mixture was stirred for 30 min andconcentrated. The crude product was purified by flash chromatography onsilica gel, eluting with a step gradient of 8:2 ethyl acetate/hexane to9:1:0.5 dichloromethane/methanol/acetic acid to give title compound as asolid (0.107 g, 48.6%)

EXAMPLE 13

[0224]

[0225] To a solution of Example 1 Part A compound (7.52 g, 20 mmol) inanhydrous tetrahydrofuran (100 mL) at −78° C. was added dropwise n-butyllithium in hexane (9.3 mL, 2.5 N, 23.25 mmol). The reaction mixture wasstirred for 15 min followed by addition of sublimed zinc bromide (5.2 g.23.1 mmol) in anhydrous tetrahydrofuran (40 mL). To this blue solutionwas added O-t-butyldimethylsilyl-3-iodophenol (6.7 g, 21.1 mmol) intetrahydrofuran (40 mL) followed by tetrakis(triphenylphosphine)palladium(0) (1.2 g, 0.96 mmol). The reaction was stirred at −78° C. for30 min and then at room temperature for 20 hr. The reaction mixture wasquenched with saturated aqueous ammonium chloride solution and extractedwith diethyl ether thrice. The combined organic layers were dried overanhydrous MgSO₄ and concentrated to get crude amber oil.

[0226] To a solution of the crude amber oil in anhydrous tetrahydrofuran(100 mL) was added dropwise tetrabutyl ammonium fluoride intetrahydrofuran (25 mL, 1 M, 25 mmol). The solution was stirred at roomtemperature for 1 hr, quenched with saturated aqueous ammonium chloridesolution and extracted with diethyl ether thrice. The combined organiclayers were washed with saturated aqueous ammonium chloride solution,dried over anhydrous MgSO₄ and concentrated. The crude product waspurified by flash chromatography on silica gel, eluting with 2:8 ethylacetate/hexane to give title compound as a yellow foam (4.6 g, 59%).

[0227] To a slurry of Part A compound (200 mg, 0.51 mmol) and cesiumcarbonate (217 mg, 0.67 mmol) in anhydrous dimethylformamide (10 mL) wasadded ethyl 2-bromopropionate (121 mg, 0.67 mmol). The reaction mixturewas stirred at room temperature for 18 h, diluted with water (20 mL),extracted with ethyl acetate (3×20 mL). The organic layer was washedwith water, and brine, then dried over anhydrous MgSO₄ and concentratedto get the crude ester as a yellow oil.

[0228] A solution of crude ester in aqueous sodium hydroxide solution (5mL, 1N) and dioxane (5 mL) was refluxed for 20 min. The reaction mixturewas cooled, concentrated, diluted with water and pH was adjusted to 1with HCl (1N). The mixture was extracted with ethyl acetate (3×20 mL).The combined organic layers were washed with water, and brine, driedover anhydrous MgSO₄ and concentrated. The crude product was purified byflash chromatography on silica gel, eluting with 75:25 ethylacetate/methanol to give title compound as a off-white powder (208 mg,88%).

EXAMPLE 14

[0229]

[0230] A solution of Example 1 Part E compound (165 mg, 0.4 mmol) inaqueous sodium hydroxide (1 mL, 10N, 10 mmol) and ethanol (3 mL) wasrefluxed for 5 h and then stirred at room temperature for 14 h. Thereaction mixture was concentrated and the residue was dissolved inwater. The pH was adjusted to 4 by acetic acid. The precipitate wasfiltered and dissolved in chloroform. The organic solution was filteredand the filtrate was concentrated to get the title compound as anoff-white solid (95 mg, 55%).

EXAMPLE 15

[0231]

[0232] To a solution of Example 1 Part C compound (75 mg, 0.18 mmol) intetrahydrofuran (4 mL) at 0° C. was added sulfamic acid (19 mg, 0.18mmol) as a solid. To this cold solution was added dropwise a solution ofsodium chlorite (20 mg, 0.18 mmol) in water (2 mL) over 10 min. Thereaction was stirred for 1 hr and then partitioned between ether andbrine. The organic layer was dried over anhydrous MgSO₄ andconcentrated. The crude product was purified by flash chromatography onsilica gel, eluting with a step gradient 2:8 ethyl acetate/hexane to5:95 methanol/dichloromethane to give title compound as a white solid(53 mg, 71%).

EXAMPLE 16

[0233]

[0234] To a solution of Example 13 Part A compound (389 mg, 1 mmol) andtriethylamine (420 μL, 3 mmol) in dichloromethane (25 mL) at 0° C. wasadded slowly triflic anhydride (185 μL, 1.1 mmol). The reaction waswarmed to room temperature over 2 hr, washed with water, dried overanhydrous MgSO₄ and concentrated. The crude product was purified byflash chromatography on silica gel, eluting with 1:4 ethylacetate/hexane to give title compound as a brown oil (485 mg, 93%).

[0235] A mixture of Part A compound (485 mg, 0.93 mmol), triethylamine(142 μL, 1.02 mmol), 1,3-bis(diphenyl-phosphino) propane (11 mg, 0.02mmol), methyl acrylate (167 μL, 1,86 mmol) and palladium acetate (5.2mg, 0.02 mmol) in dimethylformamide (10 mL) was refluxed overnight at100° C. The reaction mixture was cooled to room temperature, dilutedwith dichloromethane. The organic layer was washed with aqueous 1 N HCl,water, brine, dried over anhydrous MgSO₄ and concentrated. The crudeproduct was purified by flash chromatography on silica gel, eluting with15:85 ethyl acetate/hexane to give title compound as an off-white powder(234 mg, 55%).

[0236] A solution of Part B compound (234 mg, 0.51 mmol) in 1,4-dioxane(5 mL) and sodium hydroxide (5 mL, 1M, 5 mmol) was refluxed for 0.5 hr.The reaction mixture was cooled to room temperature, pH was adjusted to2 with HCl solution (1 M), and then extracted with ethyl acetate (2×20mL). The combined organic layers were washed water, and brine, thendried over anhydrous MgSO₄ and concentrated to give the title compoundas a white solid (198 mg, 87%). mp 190-192° C.

EXAMPLE 17

[0237]

[0238] A slurry of Example 16 Part C compound (136 mg, 0.31 mmol) and10% palladium on carbon (100 mg) in tetrahydrofuran (20 mL) was stirredunder hydrogen atmosphere overnight. The reaction was filtered andconcentrated. The residue was dissolved in ethyl acetate, washed withwater and brine, dried over anhydrous MgSO4 and concentrated to give thetitle compound as a white solid (124 mg, 90%). mp 91-93° C.

EXAMPLE 18

[0239]

[0240] 1-Methyl-3-nitro-1-nitrosoguanidine was added to a mixture ofether and aqueous potassium hydroxide solution at 0° C. The yellow etherlayer was decanted into a flask containing solid potassium hydroxidecooled to 0° C. The ether was decanted into a solution of Example 16Part B compound in dichloromethane at 0° C. Palladium acetate was addedto this mixture and the reaction was stirred for 12 h. The reactionmixture was filtered through a pad of Celite 525 and the filtrate wasconcentrated to give a brown oil. The crude product was purified byflash chromatography on silica gel, eluting with 1:4 ethylacetate/hexane to give title compound as a yellow oil (90 mg g, 92%).

[0241] A solution of Part A (90 mg, 0.203 mmol) and lithium hydroxide (9mg, 0.223 mmol) in tetrahydrofuran (5 mL) and water (5 mL) was stirredat room temperature overnight. Acidified with concentrated HCl to pH<7,extracted with ethyl acetate (3×20 mL). The combined organic layers werewashed with water, and brine, then dried over MgSO₄ and concentrated.The crude product was purified by flash chromatography on silica gel,eluting with 4:6 ethyl acetate/hexane to give title compound as a whitefoam (82 mg, 88%).

EXAMPLE 19

[0242]

[0243] To a solution of 2′-bromoacetophenone (6.7 mL, 50 mmol) andpotassium hydroxide (14.03 g, 150 mmol) in methanol (100 mL) was addedbenzaldehyde (15.3 mL, 150 mmol) at room temperature. The reactionmixture was stirred for 30 min, and poured into a mixture of acetic acidand water (1:2, 300 mL) at 0° C. The mixture was extracted withdichloromethane (3×100 mL). The combined organic layers were washed withsaturated aqueous ammonium chloride solution, brine, then dried overanhydrous MgSO₄ and concentrated. The crude product was distilled undervacuum to remove benzaldehyde. The residue was purified by flashchromatography eluting with 9:11 dichloromethane/hexane to give titlecompound as a light yellow oil (10.4 g, 72%).

[0244] A solution of Part A compound (9.18 g, 31.9 mmol), benzaldehyde(3.4 mL, 33.5 mmol), triethylamine (2.6 mL, 18.5 mmol) and3,4-dimethyl-5-(2-hydroxyethyl)thiazolium iodide (1.82 g, 6.4 mmol) inethanol (45 mL) was refluxed for 40 hr. The orange red solution wasevaporated under reduced pressure to remove ethanol. The residue wasdissolved in dichloromethane (200 mL). The organic layer was washed withdilute HCl (1M, 200 mL), saturated aqueous sodium bicarbonate solution(200 mL), water, and brine, then dried over anhydrous MgSO₄ andconcentrated. The orange red residue was purified by flashchromatography eluting with a step gradient of 50% to 66%dichloromethane in hexane to give title compound as a colorless oil(9.80 g, 78%).

[0245] A solution of Part B compound (1.31 g, 3.34 mmol) and borontrifluoride diethyl etherate (0.42 mL, 3.34 mmol) in toluene (15 mL) wasrefluxed for 3 hr. The reaction mixture was cooled to room temperatureand diluted with hexane (250 mL). The organic layer was washed withsaturated aqueous sodium bicarbonate solution (200 mL), water, andbrine, then dried over anhydrous MgSO₄ and concentrated. The lightyellow oil was purified by flash chromatography eluting 1:9dichloromethane/hexane to give title compound as a colorless oil (1.10g, 88%).

[0246] Nitrogen was bubbled through a solution of Part C compound (1.0g, 2.66 mmol), 3-methoxy phenylboronic acid (526 mg, 3.46 mmol) andsodium carbonate (9.3 mL, 2M, 18.6 mmol) in toluene (7 mL) and ethanol(2.8 mL) at room temperature for 30 min.Tetrakis(triphenylphosphine)-palladium(0) (100 mg, 0.086 mmol) was addedand the reaction mixture was stirred at 90° C. for 16 h under nitrogen.The reaction mixture was cooled to room temperature and extracted withethyl acetate (2×50 mL). The combined organic layers were washed withbrine, dried over anhydrous MgSO₄ and concentrated. The crude productwas purified by flash chromatography eluting with 1:3dichloromethane/hexane to give title compound as a white foam (1.01 g,94%).

[0247] To a mixture of Part D compound (791 mg, 1.97 mmol) and lithiumiodide (3.95 g, 29.5 mmol) was added dimethyl formamide (7 mL) at roomtemperature. The reaction mixture was refluxed at 170° C. overnightunder argon, cooled to room temperature, diluted with water andextracted with ether (3×35 mL). The combined organic layers were washedwith saturated aqueous sodium bicarbonate solution (80 mL), water, andbrine, then dried over anhydrous MgSO₄ and concentrated. The crudeproduct was purified by flash chromatography eluting with 1:3 ethylacetate/hexane to give title compound as a white foam (651 mg, 85%).

[0248] To a solution of Part E compound (368 mg, 0.95 mmol) in anhydrousdimethylformamide (2.5 mL) was added sodium hydride (38 mg, 60%, 0.95mmol). The reaction was stirred at room temperature for 20 min followedby addition of bromoacetonitrile (0.10 mL, 1.44 mmol). The reactionmixture was stirred at 50° C. overnight, cooled to room temperature,diluted with water and extracted with ether (3×40 mL). The combinedorganic layers were washed with saturated aqueous sodium bicarbonatesolution (80 mL), water, and brine, then dried over anhydrous MgSO₄ andconcentrated. The crude product was purified by flash chromatographyeluting with 1:9 dichloromethane/hexane to give title compound as awhite foam (306 mg, 75%).

[0249] A solution of Part F compound (174 mg, 0.41 mmol) andazidotrimethyltin (126 mg, 0.61 mmol) in toluene (2 mL) was refluxedovernight. The reaction mixture was cooled to room temperature, methanol(5 mL) was added, stirred for 30 min, and concentrated. The residue wasdissolved in dichloromethane (100 mL), washed with water, and brine,then dried over anhydrous MgSO₄ and concentrated. The crude product waspurified by flash chromatography eluting with 1:9 methanol/ethyl acetateto give title compound as a white solid (110 mg, 57%).

EXAMPLE 20

[0250]

[0251] A solution of Example 19 Part B compound (787 mg, 2.0 mmol) andammonium acetate (800 mg, 10.4 mmol) in acetic acid (5 mL) was refluxed,protected by a drying tube, for 3 hr. The reaction mixture was cooled toroom temperature and poured slowly into aqueous saturated sodiumbicarbonate and the reaction mixture was extracted with ethyl acetate.The organic layer was dried (MgSO₄) and concentrated. The crude productwas purified by flash chromatography on silica gel, eluting with 11:39dichloromethane/hexane, to give title compound as a white foam (508 mg,68%).

[0252] Nitrogen was bubbled through a solution of Part A compound (775mg, 2.07 mmol), 3-formyl phenylboronic acid (405 mg, 2.7 mmol) andaqueous sodium carbonate (3.3 mL, 2 M, 6.6 mmol) in toluene (5.5 mL) andethanol (2.2 mL) at room temperature for 30 min.Tetrakis(triphenylphosphine)-palladium(0) (80 mg, 0.07 mmol) was addedand the reaction mixture was stirred at 80° C. for 14 hr under argon.The reaction mixture was cooled to room temperature and extracted withethyl acetate twice. The combined organic extracts were washed withbrine, dried (MgSO₄) and concentrated. The crude product was purified byflash chromatography on silica gel, eluting with 2:1dichloromethane/hexane to give title compound as a white foam (598 mg,72%).

[0253] Lithium borohydride in tetrahydrofuran (0.5 mL, 2M, 1 mmol) wasadded slowly to a solution of Part B compound (495 mg, 1.24 mmol) intetrahydrofuran (3 mL) at room temperature under argon. The reaction wasstirred for 30 min, quenched cautiously with aqueous saturated sodiumbicarbonate solution, stirred for 10 min and extracted with ethylacetate. The organic extract was dried (MgSO₄) and concentrated. Theresidue was dissolved in dichloromethane and filtered through a pad ofsilica gel (25 g). The pad was washed with dichloromethane (200 mL). Thefiltrate was dried (MgSO₄) and concentrated to give the title compoundas a white foam (490 mg, 98%).

[0254] To a solution of Part C compound (214 mg, 0.53 mmol) and carbontetrabromide (200 mg, 0.60 mmol) in dichloromethane (2 mL) was addedtriphenylphosphine (158 mg, 0.53 mmol) at room temperature. The solutionwas stirred for 1 hr, evaporated onto silica gel and purified by flashchromatography on silica gel, eluting with 3:7 dichloromethane/hexane togive the title compound (180 mg, 73%) as a light yellow foam.

[0255] A solution of Part D compound (175 mg, 0.37 mmol) and sodiumcyanide (200 mg, 0.60 mmol) in dimethylsulfoxide (1 mL) was stirred for3 hr at 50° C. under argon. The reaction mixture was cooled to roomtemperature, diluted with water and filtered. The solid was washed withwater and dried to give the title compound as an off-white solid (140mg, 91%).

[0256] A solution of Part E compound (135 mg, 0.33 mmol) andazidotrimethyltin (100 mg, 0.49 mmol) in toluene (2 mL) was heated to140° C. for 18 hr under argon. The reaction mixture was cooled to roomtemperature. After adding methanol (5 mL), the reaction was stirred for30 min and concentrated. The crude product was purified by flashchromatography on silica gel, eluting with 1:5 methanol/dichloromethaneto give title compound as a tan solid (105 mg, 70%).

EXAMPLE 21

[0257]

[0258] A solution of Example 19 Part B compound (1.164 g, 2.96 mmol),ethylamine hydrochloride (1.22 g, 15 mmol) and sodium acetate (1.23 g,15 mmol) in acetic acid (10 mL) was refluxed for 52 h under argon. Thereaction mixture was cooled to room temperature and added slowly tosaturated aqueous sodium bicarbonate solution (100 mL). The mixture wasextracted with dichloromethane (2×100 mL) and the combined organiclayers were washed, dried (MgSO₄) and concentrated. The crude productwas purified by flash chromatography eluting with 1:7dichloromethane/hexanes to give title compound as a white foam (556 mg,47%).

[0259] Nitrogen was bubbled through a solution of Part A compound (547mg, 1.35 mmol), 3-amino phenylboronic acid (327 mg, 2.4 mmol) andaqueous sodium carbonate (3.0 mL, 2M, 6 mmol) in toluene (5 mL) andethanol (2 mL) at room temperature for 30 min.Tetrakis(triphenylphosphine)-palladium(0) (55 mg, 0.05 mmol) was addedand the reaction mixture was stirred at 80° C. for 14 h under argon. Thereaction mixture was cooled to room temperature and extracted twice withethyl acetate. The combined organic layers were washed with brine, dried(MgSO₄) and concentrated. The crude product was purified by flashchromatography eluting with 11:9 dichloromethane/hexanes to give titlecompound as a white foam (379 mg, 68%).

[0260] To a slurry of Part B compound (373 mg, 0.90 mmol) and potassiumcarbonate (200 mg, 1.4 mmol) in anhydrous DMF (2 mL) was addedbromoacetonitrile (70 RL, 1.0 mmol). The reaction mixture was stirred at50° C. overnight, cooled to room temperature, diluted with water, andextracted with ether(3×50 mL). The combined organic layers were washedwith water and brine, then dried (MgSO₄) and concentrated. The crudeproduct was purified by flash chromatography eluting with 3:7dichloromethane/hexanes to give title compound as a colorless oil (174mg, 43%).

[0261] A solution of Part C compound (120 mg, 0.38 mmol) andazidotrimethyltin (100 mg, 0.5 mmol) in toluene (2 mL) was refluxedovernight under argon. The reaction mixture was cooled to roomtemperature, methanol (5 mL) was added, stirred for 1 hr, andconcentrated to give crude title compound as a yellow oil (140 mg). Aportion of the impure product (85 mg) was purified by preparative HPLC(C-18 reverse phase, eluting with methanol/0.1% aqueous TFA) to give thetitle compound (47 mg, 34%) as a white solid, mp 109-111° C.

EXAMPLE 22

[0262]

[0263] A solution of Example 19 Part B compound (3.26 g, 8.3 mmol) andLawesson's reagent (7 g, 17 mmol) in toluene (15 mL) was refluxed for 24hr under argon. Additional Lawesson's reagent (2 g, 4.94 mmol) was addedand the solution was refluxed for an additional 24 hr. The reactionmixture was cooled to room temperature and diluted with ether. Theorganic layer was washed with saturated aqueous sodium bicarbonatesolution, water and brine, then dried (MgSO₄) and concentrated. Thecrude product was purified by flash chromatography, eluting with 1:24dichloromethane/hexanes to give title compound as a white solid (2.65 g)with the corresponding furan as an impurity (20%). The mixture wasrecrystallized from hexanes to give the product as a white solid (850mg, 93% pure, 28% yield).

[0264] Nitrogen was bubbled through a solution of Part A compound (663mg, 1.69 mmol), 3-aminophenylboronic acid (410 mg, 2.20 mmol) andaqueous sodium carbonate (3.7 mL, 2M, 7.4 mmol) in toluene (6 mL) andethanol (2.5 mL) at room temperature for 30 min.Tetrakis(triphenylphosphine)-palladium(0) (67 mg, 0.06 mmol) was addedand the reaction mixture was refluxed for 16 h under argon. The reactionmixture was cooled to room temperature, diluted with brine (10 mL) andextracted with ethyl acetate. The combined organic layers were washedwith brine, dried (MgSO₄) and concentrated. The crude product waspurified by flash chromatography, eluting with 3:1dichloromethane/hexanes to give title compound as a white foam (680 mg,100%).

[0265] To a slurry of Part B compound (354 mg, 0.878 mmol) and potassiumcarbonate (250 mg, 1.8 mmol) in anhydrous DMF (3 mL) was addedtert-butyl bromoacetate (130 μL, 0.88 mmol). The reaction mixture wasstirred at 50° C. under argon overnight, cooled to room temperature,diluted with water and extracted with ether (3×20 mL). The combinedorganic layers were washed with water and brine, then dried (MgSO₄) andconcentrated. The crude product was purified by flash chromatographyeluting with 2:3 dichloromethane/hexanes to give title compound as acolorless oil (118 mg, 26%).

[0266] A solution of Part C compound (115 mg, 0.222 mmol) intrifluoroacetic acid (1 mL) and dichloromethane (1 mL) was stirred atroom temperature for 14 h under argon. The reaction mixture wasevaporated from ethanol (4 mL) twice. The residue was dissolved in ethylacetate and hexane was added to give an oily product. The solvent wasdecanted and the product was dried under vacuum at 60° C. to give thetitle compound as a white foam (47 mg, 62%), 87% pure and containing7.8% of the analogous furan.

EXAMPLE 23

[0267]

[0268] Nitrogen was bubbled through a solution of Example 19 Part Ccompound (1.0 g, 2.66 mmol), 3-formyl phenylboronic_acid (520 mg, 3.5mmol) and aqueous sodium carbonate (9.3 mL, 2M, 18.6 mmol) in toluene (7mL) and ethanol (2.8 mL) at room temperature for 30 min.Tetrakis(triphenyl-phosphine) palladium(0) (100 mg, 0.09 mmol) was addedand the mixture was stirred at 80° C. for 14 hr under argon. Thereaction mixture was cooled to room temperature and extracted with ethylacetate (2×30 mL). The combined organic extracts were washed with brine,dried (MgSO₄) and concentrated. The crude product was purified by flashchromatography on silica gel, eluting with 1:3 dichloromethane/hexane togive title compound as a white foam (525 mg, 49%).

[0269] Lithium aluminum hydride in tetrahydrofuran (0.7 mL, 1M, 0.7mmol) was added slowly to a solution of Part A compound (494 mg, 1.23mmol) in tetrahydrofuran (3 mL) at room temperature under argon. Thereaction was stirred for 15 min, quenched cautiously with aqueouspotassium hydrogen sulfate solution (5%) and extracted with ethylacetate. The organic layer was dried (MgSO₄) and concentrated to givethe title compound as a white foam (471 mg, 95%).

[0270] To a solution of Part B compound (465 mg, 1.15 mmol),triphenylphosphine (303 mg, 1.16 mmol) and imidazole (172 mg, 2.5 mmol)in tetrahydrofuran (5 mL) under argon was added a solution of iodine(293 mg, 1.15 mmol) in THF (1 mL) over 5 min. The reaction mixture wasstirred for 10 min and then diluted with ethyl acetate. The organiclayer was washed with sodium bisulfite solution (5%), dried (MgSO₄) andconcentrated. The crude product was purified by flash chromatography onsilica gel, eluting with hexane to give title compound as a colorlessoil (304 mg, 51%).

[0271] A solution of Part C compound (299 mg, 0.584 mmol) and potassiumcyanide (300 mg, 4.6 mmol) in DMSO (3 mL) was stirred at 50° C. for 13h. The reaction mixture was cooled to room temperature, diluted withwater, and extracted with diethyl ether (3×20 mL). The organic layer wasdried (MgSO₄) and concentrated to give the title compound as a yellowoil (193 mg, 80%).

[0272] A solution of Part D compound (190 mg, 0.46 mmol) andazidotrimethyltin (140 mg, 0.68 mmol) in toluene (3 mL) was refluxed for18 h under argon. The reaction mixture was cooled to room temperature,methanol (5 mL) was added and the mixture was stirred for 30 min. Afterevaporating the solvents, the crude product was recrystallized fromethyl acetate/hexane to give title compound as a white solid (77 mg,37%), mp 188-190° C.

EXAMPLE 24

[0273]

[0274] To a solution of 2-bromo-3-methyl benzoic acid (2.15 g, 10 mmol),4-dimethyl amino pyridine (211 mg, 1.73 mmol) and benzoin (2.07 g, 9.56mmol) in dichloromethane (30 mL) was added1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (2.09 g,10.6 mmol) at room temperature. The resulting pale yellow solution wasstirred for 48 hr, treated with HCl (20 mL, 0.5 N) and extracted withethyl acetate (2×150 mL). The combined organic layers were washed withHCl (20 mL, 0.5 N), saturated sodium bicarbonate solution (20 mL), andbrine (20 mL), dried over anhydrous MgSO₄ and concentrated. The crudeproduct was purified by flash chromatography on silica gel, eluting with5:95 ethyl acetate/hexane to give the ketoester as a colorless oil (2.83g, 67%).

[0275] A mixture of crude ketoester (2.81 g, 6.9 mmol) and ammoniumacetate (2.63 g, mmol) in glacial acetic acid (25 mL) was stirred at110° C. for 4 h. The reaction mixture was concentrated to half thevolume, cooled to 0° C. and diluted with water. The mixture wasextracted with ethyl acetate (2×150 mL). The combined organic layerswere washed with water (3×30 mL), saturated aqueous sodium bicarbonatesolution (2×30 mL), and brine(30 mL), dried over anhydrous MgSO₄ andconcentrated. The crude product was purified by flash chromatography onsilica gel, eluting with 5:95 ethyl acetate/hexane to give titlecompound as a white solid (2.46 g, 91%). mp 83-85° C.

[0276] To a solution of Part A compound (500 mg, 1.28 mmol) in anhydroustetrahydrofuran (7 mL) at −78° C. was added dropwise n-butyl lithium inhexane (600 μL, 2.5 N, 1.47 mmol). The reaction mixture was stirred for15 min followed by addition of zinc bromide (330 mg, 1.47 mmol) inanhydrous tetrahydrofuran (3.3 mL). To this light green solution wasadded 1-(t-butyldimethylsilyloxy)-3-iodobenzene (428 mg, 1.37 mmol) intetrahydrofuran (1 mL) followed by tetrakis(triphenylphosphine)palladium(0) (74 mg, 0.06 mmol). The reaction was stirred at −78° C. for30 min and then at room temperature for 20 h. The reaction was quenchedwith aqueous ammonium chloride solution (5 mL, 25%) and extracted withdiethyl ether (2×25 mL). The combined organic layers were washed withaqueous ammonium chloride solution (5 mL, 25%), brine (5 mL), dried overanhydrous MgSO₄ and concentrated. The crude product was purified byflash chromatography on silica gel, eluting 2:98 ethyl acetate/hexane togive title compound as a syrup (229 mg, 34.6%).

[0277] To a solution of Part B compound (229 mg, 0.44 mmol) in anhydroustetrahydrofuran(4 mL) was added dropwise tetrabutylammonium fluoride intetrahydrofuran (400 μL, 1 M, 0.4 mmol). The yellow solution was stirredat room temperature for 72 h, quenched with aqueous ammonium chloridesolution (2 mL, 25%) and extracted with diethyl ether (2×25 mL). Thecombined organic layers were washed with aqueous ammonium chloridesolution (2 mL, 25%), dried over anhydrous MgSO₄ and concentrated. Thecrude product was purified by flash chromatography on silica gel,eluting with a step gradient of 2:98 to 5:95 ethyl acetate/hexane togive title compound as a syrup (163 mg, 92%).

[0278] To a slurry of Part C compound (41 mg, 0.10 mmol) and potassiumcarbonate (25 mg, 0.18 mmol) in anhydrous dimethylformamide (0.5 mL) wasadded ethyl bromoacetate (15 μL, 0.14 mmol). The reaction mixture wasstirred at room temperature for 20 h, diluted with ethyl acetate (20mL). The organic layer was washed with water (3×1 mL), and brine (1 mL),then dried over anhydrous MgSO₄ and concentrated. The crude ester wasused directly for the next step.

[0279] A solution of Part D (41 mg, 0.084 mmol) compound and sodiumhydroxide solution (250 μL, 1N, 0.25 mmol) in methanol (1 mL) and water(1 mL) was stirred at room temperature for 1.5 h. The reaction mixturewas concentrated, diluted with water and HCl (200 μL, 1N), extractedwith ethyl acetate (2×10 mL). The combined organic layers were washedwith water (2×1 mL), and brine (1 mL), dried over anhydrous MgSO₄ andconcentrated to give the title compound as a beige foam (41 mg, 100%).

EXAMPLE 25

[0280]

[0281] A solution of Example 1 Part A compound (1.25 g, 3.22 mmol) andtetrakis(triphenylphosphine) palladium(0) (117 mg, 0.10 mmol) in toluene(7.5 mL) was stirred for 10 min. 3-Aminophenyl boronic acid(637 mg, 3.96mmol) was added to the solution followed by aqueous sodium carbonate(3.3 mL, 2M, 6.6 mmol). The reaction mixture was stirred at 80° C. for20 hr under argon, cooled to room temperature and concentrated. Theresidue was partitioned between ethyl acetate (2×90 mL) and water (9mL). The combined organic layers were washed with brine, dried overanhydrous MgSO₄ and concentrated. The crude product was purified byflash chromatography on silica gel, eluting with a step gradient of 1:9to 1:4 ethyl acetate/hexane to give title compound as an oil (1.445 g,100%).

[0282] The mixture of Part A compound (1.445 g, 3.22 mmol),diisopropylethylamine (1.12 mL, 6.44 mmol), and benzylbromoacetate (610μL, 3.7 mmol) in anhydrous dimethylformamide (15 mL) was stirred at roomtemperature for 17 hr. The reaction mixture was diluted with ethylacetate (250 mL). The organic layer was washed with water (3×40 mL),brine (40 mL), dried over anhydrous MgSO₄ and concentrated. The crudeproduct was purified by flash chromatography on silica gel, eluting witha step gradient of 1:9 to 1:4 ethyl acetate/hexane to give titlecompound as an oil (1.57 g, 91%).

[0283] To a slurry of Part B compound (100 mg, 0.19 mmol) and potassiumcarbonate (26 mg, 0.19 mmol) in anhydrous dimethylformamide (1 mL) wasadded methyl iodide (17 μL, 0.28 mmol). The reaction mixture was stirredat room temperature for 16 h. Additional methyl iodide (60 μL, 0.99mmol) was added and the reaction was stirred for 24 hr. Methyl iodide(40 μL, 0.66 mmol) was added again and the reaction was stirred for 20hr. The reaction mixture was diluted with ethyl acetate (25 mL). Theorganic layer was washed with water (3×2 mL), and brine (2 mL), thendried over anhydrous MgSO₄ and concentrated. The golden oil was purifiedby flash chromatography on silica gel, eluting with 1:9 ethylacetate/hexane to give title compound as colorless oil (73 mg, 70%).

[0284] A suspension of Part C compound (73.5 mg, 0.13 mmol) and 20%palladium hydroxide on carbon (12.9 mg) in ethyl acetate (3 mL) wasstirred under hydrogen atmosphere (1 atm) for 5 h. Additional catalyst(12 mg) was added and the reaction was stirred for 5 h. The reactionmixture was filtered through a pad of Celite® 525. The solids werewashed with ethyl acetate (2×10 mL) and concentrated. The crude productwas purified by flash chromatography on silica gel, eluting with a stepgradient of 1:4 ethyl acetate/hexane to 95:5 dichloromethane/methanol togive title compound as a foam (14 mg, 24%).

EXAMPLE 26

[0285]

[0286] A solution of Example 24 Part A compound (700 mg, 1.79 mmol) andtetrakis(triphenylphosphine) palladium(0) (63 mg, 0.055 mmol) in toluene(4 mL) was stirred for 10 min. 3-aminophenyl boronic acid (344 mg, 2.15mmol) was added to the solution followed by aqueous sodium carbonate(1.8 mL, 2M, 3.6 mmol). The reaction mixture was stirred at 80° C. for20 h under argon, cooled to room temperature and concentrated. Theresidue was partitioned between dichloromethane (2×50 mL) and water (5mL). The combined organic layers were washed with brine, dried overanhydrous MgSO₄ and concentrated. The crude product was purified byflash chromatography on silica gel, eluting with 1:9 ethylacetate/hexane to give title compound as a white foam (623 mg, 86%).

[0287] The mixture of Part A compound (300 mg, 0.72 mmol),diisopropylethylamine (0.25 mL, 1.44 mmol), and benzylbromoacetate (130μL, 0.79 mmol) in anhydrous dimethylformamide (3 mL) was stirred at roomtemperature for 20 hr. The reaction mixture was diluted with ethylacetate (100 mL). The organic layer was washed with water (2×10 mL),brine (10 mL), dried over anhydrous MgSO₄ and concentrated. The crudeproduct was purified by flash chromatography on silica gel, eluting witha step gradient of 5:95 to 1:9 ethyl acetate/hexane to give titlecompound as a white foam (341 mg, 86%).

[0288] A suspension of Part B compound (311 mg, 0.56 mmol) and 20%palladium hydroxide on carbon (50 mg) in ethyl acetate (10 mL) wasstirred under hydrogen atmosphere (1 atm) for 5 h. The reaction mixturewas filtered through a pad of Celite® 525. The solids were washed withethyl acetate (3×10 mL) and concentrated. The crude product wastriturated with 1:5 dichloromethane/pentane (25 mL) to give the titlecompound as an off-white precipitate which was washed with pentane anddried (222 mg, 86%). mp 175-177° C.

EXAMPLE 27

[0289]

[0290] To a solution of 2-(3-nitro-p-toluyl)-benzoic acid (325 mg, 1.26mmol), 4-dimethylaminopyridine (41 mg, 0.34 mmol) and benzoin (404 mg,1.90 mmol) in dichloromethane (6 mL) was added1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (408 mg,2.09 mmol) at room temperature. The resulting pale yellow solution wasstirred for 16 h, treated with HCl (4 mL, 0.5 N) and extracted withethyl acetate (2×30 mL). The combined organic layers were washed withHCl (4 mL, 0.5 N), saturated sodium bicarbonate solution (4 mL), andbrine (4 mL), dried over anhydrous MgSO₄ and concentrated to give alight yellow oil.

[0291] A mixture of crude ketoester and ammonium acetate (500 mg, 6.49mmol) in glacial acetic acid (5 mL) was stirred at 105° C. for 4 h. Thereaction mixture was concentrated and extracted with ethyl acetate (2×50mL). The combined organic layers were washed with water (3×12 mL),saturated aqueous sodium bicarbonate solution (2×12 mL), and brine (7mL), dried over anhydrous Na₂SO₄ and concentrated. The crude product waspurified by flash chromatography on silica gel, eluting with 5:95 ethylacetate/hexane to give title compound as a white foam (265 mg, 48%). mp108-110° C.

[0292] A suspension of Part A compound (265 mg, 0.61 mmol) and 20%palladium hydroxide on carbon (50 mg) in ethyl acetate (10 mL)) wasstirred under hydrogen atmosphere (1 atm) for 41 h. The reaction mixturewas filtered through a pad of Celite® 525. The solids were washed withethyl acetate (3×10 mL) and concentrated. The crude product was purifiedby flash chromatography on silica gel, eluting with a step gradient of5:95 to 1:9 ethyl acetate/hexane to give title compound as a white foam(259 mg, 100%).

[0293] The mixture of Part B compound (255 mg, 0.63 mmol),diisopropylethylamine (0.22 mL, 1.26 mmol), and benzylbromoacetate (120μL, 0.72 mmol) in anhydrous dimethylformamide (3 mL) was stirred at roomtemperature for 20 h. The reaction mixture was diluted with ethylacetate (250 mL). The organic layer was washed with water (3×8 mL),brine (8 mL), dried over anhydrous MgSO₄ and concentrated. The crudeproduct was purified by flash chromatography on silica gel, eluting with1:9 ethyl acetate/hexane to give title compound as a white foam (226 mg,65%).

[0294] A suspension of Part C compound (226 mg, 0.41 mmol) and 20%palladium hydroxide on carbon (37 mg) in ethyl acetate (7.5 mL)) wasstirred under hydrogen atmosphere (1 atm) for 5 h. The reaction mixturewas filtered through a pad of Celite® 525. The solids were washed withethyl acetate (3×10 mL) and concentrated. The crude product wastriturated with 1:4 dichloromethane/hexane (25 mL) to get the titlecompound as a cream colored precipitate which was washed with hexane anddried (188 mg, 100%). mp 182-184° C.

EXAMPLE 28

[0295]

[0296] 2-Bromobenzoyl chloride (15.2 mL, 0.118 mol) was added dropwiseto a stirred solution of phenyl hydrazine (11.6 mL, 0.118 mol) andtriethylamine (16.0 mL, 0.115 mol) in ether (400 mL) at 0° C. over 30min. The reaction was warmed to room temperature. The solids formed werefiltered and washed with ether thrice. The solids were dissolved indichloromethane washed with water, and brine, dried over anhydrous MgSO4and concentrated. The crude was recrystalized from ethyl acetate to getthe title compound (12.1 gm, 35%)

[0297] A solution of Part A compound (5 gm, 17.2 mmol) and phosphoruspentachloride (4.22 gm, 19.3 mmol) in ether (100 mL) was refluxed for 19hr. The reaction mixture was cooled to room temperature and treated witha solution of phenol (7.38 gm, 78.4 mmol) in ether (10 mL). After 10min, methanol (7.3 mL) was added, the mixture was stirred for 5 min andconcentrated. The residue was purified by flash chromatography on silicagel eluting with 10% EtOAc in hexane to give title compound as a lightbrown 0:1 (2.07 g, 39%).

[0298] A solution of Part B compound (2.0 gm, 6.46 mmol) in absoluteethanol (9.4 mL) was added to a solution of ethylbenzoyl acetate (1.26mL, 6.55 mmol) and 21% sodium ethoxide in ethanol (2.09 mL, 6.44 mmol)in absolute ethanol (12.6 mL). The reaction was stirred at roomtemperature for 4 h, quenched with 2N HCl (7.5 mL) and concentrated. Theresidue was triturated with ether. The organic layer was washed withwater, and brine, dried over anhydrous MgSO4 and concentrated. Theresidue was purified by flash chromatography on silica gel eluting witha step gradient of 5% to 10% EtOAc in hexane to give the title compoundas a thick oil (1.1 g, 38%).

[0299] Nitrogen was bubbled through a solution of Part C compound (1.145g, 2.56 mmol), 3-methoxyphenyl boronic acid (478 mg, 3.15 mmol) andaqueous sodium carbonate (2.6 mL, 2M, 5.2 mmol) in toluene (6 mL) andethanol (2.6 mL) at room temperature for 15 min.Tetrakis(triphenylphosphine) palladium(0) (93 mg, 0.08 mmol) was addedand the mixture was stirred at 80° C. for 20 h under argon. The reactionmixture was cooled to room temperature, diluted with water and extractedwith ethyl acetate. The combined organic extracts were washed withbrine, dried over anhydrous MgSO4 and concentrated. The crude productwas purified by flash chromatography on silica gel, eluting with a stepgradient of 5% to 10% ethyl acetate in hexane to give the title compound(1.215 g, 100%).

[0300] To a solution of Part D compound (948 mg, 1.99 mmol) in drydichloromethane (10 mL) at 0° C. was added boron tribromide indichloromethane (1M, 4.1 mL, 4.1 mmol). The reaction was stirred at 0°C. for 3 h and the at room temperature overnight. The mixture wasdiluted with water followed by 1N HCl and extracted with ethyl acetate.The combined organic extracts were washed with brine, dried overanhydrous MgSO4 and concentrated. The crude product was purified byflash chromatography on silica gel, eluting with a step gradient of 10%to 50% ethyl acetate in hexane to give title compound (688 mg, 75%).

[0301] A solution of Part E compound (670 mg, 1.45 mmol) in anhydrousether (3.6 mL) was added to a slurry of lithium aluminium hydride (114mg, 2.85 mmol) in anhydrous ether (6 mL) at 0° C. The reaction wasstirred at 0° C. for 3 h and at room temperature for 4 h. Anhydrous THF(10 mL) was added to the reaction mixture and it was stirred for 4 h.The reaction was cooled to 0° C. and quenched with 10% HCl and extractedwith ethyl acetate. The combined organic extracts were washed withbrine, dried over anhydrous MgSO4 and concentrated. The crude productwas purified by flash chromatography on silica gel, eluting with a stepgradient of 10% to 20% to 50% ethyl acetate in hexane to give the titlecompound (474 mg, 78%).

[0302] To a slurry of Part F compound (472 mg, 1.13 mmol) and potassiumcarbonate (180 mg, 1.3 mmol) in anhydrous dimethylformamide (5 mL) wasadded ethyl bromoacetate (150 μL, 1.3 mmol). The reaction mixture wasstirred at room temperature for 48 h, diluted with ethyl acetate andwater. The organic layer was washed with water and brine, then driedover anhydrous MgSO₄ and concentrated. The crude was purified by flashchromatography on silica gel, eluting with a step gradient of 25% to 33%ethyl acetate in hexane to give the title compound as an oil (410 mg,74%).

[0303] A solution of Part G compound (60 mg, 0.12 mmol) in aqueoussodium hydroxide (350 μL, 1N, 3.5 mmol) and methanol (1.4 mL) was heatedto 50° C. for 3 h. The reaction mixture was concentrated and the residuewas diluted with water. The pH was adjusted to 1 with 1N HCl. Themixture was extracted with ethyl acetate. The combined organic layerswere washed with brine, dried over anhydrous MgSO₄ and concentrated togive title compound as a foam (63.8 mg, 100%).

EXAMPLE 29

[0304]

[0305] A solution of

[0306] generated in analogy to the procedure used in Example 28 Part B,(2 g, 6.46 mmol) in anhydrous benzene (10 mL) was added to a solution ofaniline (650 μL, 7.13 mmol) and triethyl amine (970 μL, 6.96 mmol) inanhydrous benzene (10.8 mL) at 50° C. The reaction was stirred at 50° C.for 3 hrs and concentrated. The residue was partitioned between waterand ethyl acetate. The organic layer was washed with brine, dried overanhydrous MgSO4 and concentrated. The crude product was purified byflash chromatography on silica gel, eluting with 5% ethyl acetate inhexane to give title compound (1.328 g, 57%).

[0307] A solution of Part A compound (200 mg, 0.55 mmol) and triphosgene(248 mg, 0.82 mmol) in pyridine (600 μL) was heated to 160° C. in asealed tube for 1 min. The reaction was cooled to room temperature andpartitioned between water and ethyl acetate. The organic layer waswashed with brine, dried over anhydrous MgSO4 and concentrated. Thecrude product was purified by flash chromatography on silica gel,eluting with 25% ethyl acetate in hexane to give title compound (203 mg,94%).

[0308] Following the same experimental procedure as in Example 28 PartD, coupling between Part B compound and 3-amino phenyl boronic acidafforded the title compound (yield 99%).

[0309] Following the same experimental procedure as in Example 28 PartG, alkylation of Part C compound with ethyl bromoacetate afforded thetitle compound (yield 34%).

[0310] Following the same experimental procedure as in Example 28 PartH, hydrolysis of Part D compound afforded the title compound (yield90%).

EXAMPLE 30

[0311]

[0312] Following the same experimental procedure as in Example 28 PartD, the Suzuki coupling between Example 29 Part B compound and 3-methoxyphenyl boronic acid afforded the title compound (yield 87%).

[0313] Following the same experimental procedure as in Example 28 PartE, Part A compound was treated with boron tribromide to afford the titlecompound (yield 73%).

[0314] Following the same experimental procedure as in Example 28 PartG, alkylation of Part B compound with ethyl bromoacetate afforded thetitle compound (yield 96%).

[0315] Following the same experimental procedure as in Example 28 PartH, hydrolysis of Part C compound afforded the title compound as a whitesolid (yield 98%).

EXAMPLE 31

[0316]

[0317] Example 1 Part A compound was coupled with 2-formyl-phenylboronic acid by Suzuki coupling procedure described in Example 1 Part Bto give the title compound in 84% yeild.

[0318] Triethyl phosphonoacetate (0.27 mL, 1.37 mmol) was added dropwiseto a stirred suspension of sodium hydride (33 mg, 1.37 mmol) in THF (2mL). The mixture was stirred for 1 hr, followed by dropwise addition ofPart B compound (500 mg, 1.24 mmol) in THF(2 mL). The resulting yellowsolution was stirred at room temperature overnight. Additional sodiumhydride (20 mg, 0.83 mmol) was added and the reaction was stirred for 1h. The reaction was diluted with water (50 mL) and ether(30 mL). Theaqueous layer was extracted with ether twice. The combined organiclayers were washed with brine dried over MgSO4 and concentrated to givethe title compound (528 mg, 90%) which was used without purification inthe next step.

[0319] A mixture of Part B compound (100 mg, 0.212 mmol) in THF (1 mL)was treated with 1N NaOH solution (0.424 mL, 0.424 mmol). Afterrefluxing overnight, the mixture was concentrated, and diluted withethyl acetate/water. The reaction mixture was acidified with 1N HCl topH of 1. The resulting light yellow precipitate was filtered, washedwith hexane and water. The solid was purified by flash chromatography onsilica gel eluting with 1:1 hexane:ethyl acetate to give title compound(42 mg, 45%).

EXAMPLE 32

[0320]

[0321] A suspension of Example 31 Part B compound (100 mg, 0.212 mmol)and 20% palladium on carbon (20 mg) in methanol was stirred underhydrogen (1 atm) overnight. The reaction mixture was filtered through apad of Celite(545 and the filtrate was concentrated. The residue waspurified by flash chromatography on silica gel eluting with a stepgradient of 5% to 10% EtOAc in hexane to give title compound (92 mg,92%).

[0322] A mixture of Part A compound (90 mg, 0.190 mmol) in THF (0.5 mL)was treated with 1N NaOH solution (0.380 mL, 0.380 mmol). After stirringovernight at RT, the mixture was concentrated, diluted with water. Thereaction mixture was acidified with 1N HCl to pH of 1. The tanprecipitate was filtered, washed with hexane and water. The solid wasdried to give the title compound (60 mg, 71%).

EXAMPLE 33

[0323]

[0324] To a solution of Example 31 Part A compound (200 mg, 0.49 mmol)in THF (1.5 mL) and water (0.5 mL) at 0° C. was added sulfamic acid (48mg, 0.49 mmol) and sodium chlorite (45 mg, 0.49 mmol). The reaction wasstirred for 1.5 h and diluted with ether. The organic layer was washedwith water, brine, dried over anhydrous MgSO4 and concentrated. Thecrude material was purified by preparative reverse phase HPLC to givethe title compound (65 mg, 31%).

EXAMPLE 34

[0325]

[0326] A mixture of 3-bromophenol (20 g, 116 mmol), K₂CO₃ (31.95 g,231.2 mmol) and DMF (120 mL) was treated with tert-butyl bromoacetate(20 mL, 231 mmol) and the mixture stirred for 16 h. The reaction wasconcentrated and the residue was dissolved in ethyl actate. The organicfraction was washed with water, brine, dried (MgSO4) and concentrated.The residue was purified by flash column chromatography on silica geleluting with 5% ethyl acetate in hexane to give the title compound as acolorless oil (30 g, 100%).

[0327] Part A compound was coupled with 2-formyl phenyl boronic acid bySuzuki coupling procedure described in Example 5 Part C to give thetitle compound in 69% yeild.

[0328] A mixture of benzil (5.5 g, 26.4 mmol) and ammonium acetate(12.94 g, 168 mmol) in glacial acetic acid (120 mL) was treated withPart B compound (7.5 g, 24.0 mmol) and stirred at 120° C. for 15 h. Thereaction mixture was cooled, poured in water (300 mL) and precipitatewas filtered. The solid was washed with hexane and dried to give thetitle compound as an off-white solid (12 g, 100%).

EXAMPLE 35

[0329]

[0330] A solution of Example 34 compound (11.5 g, 22.8 mmol) in ethanol(300 mL) and sulfuric acid (3 mL) was stirred at room temperatureovernight. The reaction was concentrated, diluted with ethyl acetate andneutralized with aqueous sodium carbonate solution. The organic layerwas washed with water, aqueous sodium carbonate, and brine, dried overanhydrous MgSO4 and concentrated. The crude was triturated with hexaneand ether to give the title compound as a light yellow solid (9.13 g,84%).

[0331] A mixture of Part A compound (0.100 g; 0.210 mmol), K2CO3 (0.058g; 0.421 mmol) and DMF (1 mL) was treated with allyl bromide (20 μL,0.231 mmol) and the mixture stirred for 16 h. Additional allyl bromide(20 μL, 0.023 mmol) was added. The mixture was stirred for 2 h. Themixture was diluted with equal amounts of ethyl acetate and water. Theorganic fraction was washed with water, brine, dried (MgSO4) andconcentrated. The residue was purified by flash column chromatographywith a step gradient of 10% to 20% ethyl acetate in hexane to give thetitle compound as a colorless oil. (0.095 g, 88%).

[0332] A mixture of Part B compound (0.095 g, 0.184 mmol) in methanol(0.5 mL) and THF (0.5 mL) was treated with 1N NaOH solution (0.276 mL,0.276 mmol). After stirring overnight at RT, the mixture wasconcentrated, diluted with ethyl acetate. The reaction mixture wasacidified with 1N HCl to pH of 1. The layers were equilibrated andseparated. The organic fraction was washed with brine, dried over MgSO4,and concentrated. The crude was recrystallized from ethylacetate/hexane/dichloromethane to give the title compound as a whitesolid (0.032 g, 36%).

EXAMPLE 36

[0333]

[0334] A mixture Example 5 Part A compound (3.75 g; 10.0 mmol) andsodium hydride (0.24 g, 10.0 mmol) in 35 mL of THF was stirred at RT for15 min. The anion was slowly treated with methyl iodide (1.42 g, 10.0mmol) and stirred overnight. The mixture was diluted with equal amountsof water and ethyl acetate. The layers were equilibrated. The organicfraction was washed with water (2×20 mL), brine, dried over MgSO4 andconcentrated under vaccuum to give a white solid. The solid wasrecrystalized from hot methanol to give 2 g of product. The motherliquor was concentrated and recrystalized from methanol and a trace ofwater to give 1 g of additional material. The white solid was combinedto give the title compound (3 g, 77%).

[0335] A mixture of 3-bromophenol (5 g, 29.0 mmol), potassium carbonate(4.0 g, 29.0 mmol) and benzyl bromide (4.87 g, 28.5 mmol) in 40 mL ofDMF was stirred at RT for 18 hr. The mixture was diluted with water, thepH adjusted to 12 with KOH (pellets) and a white solid formed. The solidwas triturated with water, filtered and washed with water to give thetitle compound (7.20 g, 96%).

[0336] A mixture of Part B compound (3.20 g, 12.16 mmol) in 24 mL of THFat −78° C. was treated with n-butyllithium (5.8 mL, 14.6 mmol). After 1h at −78° C. the anion was slowly treated with triisopropyl borate (2.28g, 12.18 mmol) and the mixture warmed to RT. The mixture was dilutedwith a 3% acetic acid/water solution (60 mL). The mixture was stirredfor 40 min. and the solid which formed was collected. The solid wastriturated with a small volume of 5% ethyl acetate/hexane to give thetitle compound as a white powder (0.5 g, 18%).

[0337] Following the general experimental procedure as in Example 8 PartA, Suzuki coupling between Part A and Part C compound afforded the titlecompound (yield 60%).

[0338] A mixture of Part D compound (0.50 g, 1.0 mmol) in ethanol (7 mL)was degassed and treated with 100 mg of 10% Pd on carbon. The mixturewas put under an atmosphere of hydrogen gas (balloon pressure) andstirred overnight. The mixture was filtered and the colorless solutionwas mixed with 100 mg of Pearlman's catalyst and placed under anatmosphere of hydrogen for 4 h. The reaction was filtered and thefiltrate concentrated to an oil. The oil was used without furtherpurification.

[0339] A mixture of the crude Part E compound (1 mmol), K2CO3 (0.138 g,1.0 mmol) and ethyl bromoacetate (0.14 g, 0.8 mmol) in dimethylformamide (3 mL) was stirred at RT overnight. The contents were dilutedwith equal amounts of water and ethyl acetate. The organic fraction wasdried (MgSO4) and concentrated to provide a thick oil. The oil waspurified on silica gel by flash column chromatography with 15% ethylacetate:hexanes to give 0.28 g of crude material. The material wasrechromatographed on silica with 7% ethyl acetate/dichloromethane togive the title compound (0.18 g, 36%).

[0340] The Part F compound (0.18 g, 0.36 mmol) was dissolved in ethanol(2 mL) and treated with 1N NaOH (2 mL, 2 mmol). After 18 h at RT themixture was acidified with citric acid until a pH of 3 was achieved. Themixture was diluted with equal volumes of ethyl acetate and water. Thelayers were equilibrated and the organic fraction dried (Na2SO4) andconcentrated to give the title compound as a (0.17 g, 100%).

EXAMPLE 37

[0341]

[0342] A mixture of Example 5 Part A compound (0.75 g, 2 mmol) in 5 mLof DMF at RT was treated with K₂CO (0.28 g, 2 mmol) and n-propyl iodide(0.3 mL, 3 mmol). The mixture was stirred for 18 h and poured intowater. The water fraction was decanted from the thick residue. Theresidue was triturated with EtOH/water and the remainder was dried undervacuum to give the title compound as a white foam (380 mg, 50%).

[0343] Nitrogen was bubbled through a solution of Part A compound (350mg, 0.84 mm ol), 3-amino phenyl boronic acid (172 mg, 1.26 mmol) andaqueous sodium carbonate (840 μL, 2M, 1.68 mmol) in toluene (1.3 mL) andethanol (700 μL) at room temperature for 15 min.Tetrakis(triphenylphosphine) palladium(0) (50 mg, 0.04 mmol) was addedand the mixture was stirred at 80° C. for 36 h under argon. The reactionmixture was cooled to room temperature and extracted with ethyl acetate.The combined organic extracts were washed with brine, dried overanhydrous MgSO₄ and concentrated. The crude product was purified byflash chromatography on silica gel, eluting with 35:65 ethylacetate/hexane to give title compound (310 mg, 88%).

[0344] To a slurry of Part B compound (680 mg, 1.57 mmol) and potassiumcarbonate (420 mg, 3 mmol) in anhydrous dimethylformamide (3 mL) wasadded ethyl bromoacetate (250 mg, 1.50 mmol). The reaction mixture wasstirred at room temperature for 18 h. The reaction was partitionedbetween diethyl ether and aqueous sodium bicarbonate solution. Theorganic layer was washed with water, and brine, then dried overanhydrous MgSO₄ and concentrated. The crude product was purified byflash chromatography eluting with 3:7 ethyl acetate/hexane to give titlecompound (450 mg, 55%).

[0345] A mixture of Part C compound (0.35 g, 0.67 mmol) in methanol (3mL) was treated with 1M NaOH solution (2 mL, 2 mmol). After stirring for3 h at RT the mixture was diluted with ether and citric acid was addeduntil the aqueous fraction maintained a pH of 3. The layers wereequilibrated and separated. The organic fraction was dried over MgSO4,and concentrated to give the title compound (0.33 g, 100%).

EXAMPLE 38

[0346]

[0347] Followed the same experimental procedure as described in Example37 Part B using Example 5 Part A compound and 3-amino phenyl boronicacid to give the title compound (yield 50%).

[0348] The experimental procedure as set out in Example 37 Part Cemploying the above Part B compound was followed to give the titlecompound (yield 55%).

[0349] The experimental procedure as set out in Example 37 Part Demploying the above Part B compound was followed to give the titlecompound (yield 75%).

EXAMPLE 39

[0350]

[0351] The experimental procedure as set out in Example 37 Part B wasfollowed for Suzuki coupling between the Example 36 Part A compound and3-amino phenyl boronic acid to give the title compound (yield 76%).

[0352] The experimental procedure as set out in Example 37 Part Cemploying the above Part B compound was followed to give the titlecompound (yield 75%).

[0353] The experimental procedure as set out in Example 37 Part Demploying the above Part B compound was followed to give the titlecompound (yield 60%).

EXAMPLE 40

[0354]

[0355] A mixture of Example 34 Part B compound (1.20 g, 3.84 mmol) in 10mL of a 3:1 THF:water solution in ice bath was treated sequentially withsulfamic acid (1.31 g, 13.6 mmol) and sodium chlorite (1.22 g, 13.6mmol). After 15 min the mixture was warmed to RT for 1 h and dilutedwith equal amounts of water and ether. The layers were equilibrated andthe organic fraction washed with brine, dried (MgSO4) and concentratedto give the title compound (1.20 g, 95%).

[0356] A mixture of Part A compound (0.53 g, 1.61 mmol), potassiumcarbonate (0.23 g, 1.70 mmol) and (a-bromo-acetophenone (0.29 g, 1.70mmol) in 4 mL of DMF was stirred at RT overnight. The mixture wasdiluted with equal amounts of water and ether. The layers wereequilibrated. The organic fraction was washed with water (2×20 mL),brine, dried over MgSO4 and concentrated under vacuum. The crude productwas purified by flash chromatography on silica gel, eluting with 15:85ethyl acetate/hexane to give title compound (590 mg, 82%).

[0357] A mixture of Part B compound (0.59 g, 1.33 mmol) in 4 mL ofacetic acid with ammonium chloride (0.60 g, 7.8 mmol) was heated toreflux for 48 h. The mixture was diluted with equal amounts of water andethyl acetate. The organic fraction was washed with water, dried (MgSO4)and concentrated. The residue was purified by flash chromatography onsilica gel eluting with 3:97:0.1 THF:dichloromethane:acetic acid to givetitle compound (70 mg, 14%).

EXAMPLE 41

[0358]

[0359] A solution of Example 40 Part A compound (0.32 g, 1 mmol),4-dimethylamino pyridine (0.04 g, 0.3 mmol),1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (0.23 g,1.20 mmol) and 2-pyridoin (0.21 g, 1.0 mmol) in dichloromethane (3 mL)was stirred at room temperature for 4 hr. The reaction mixture waswashed with water, brine, dried over anhydrous MgSO₄ and concentrated.The crude product was purified by flash chromatography on silica gel,eluting with 3:7 ethyl acetate/hexane to give title compound (0.096 g,20%).

[0360] A mixture of Part A compound (0.096 g, 0.18 mmol) in 2 mL ofacetic acid with ammonium chloride (0.096 g, 1.2 mmol) was heated toreflux for 4 h. The mixture was stripped under reduced pressure to anoil. The oil was purified on reverse phase column chromatography. Thepure fractions were combined and concentrated to give the title compound(10 mg, 13%).

EXAMPLE 42

[0361]

[0362] A solution of 2-iodo-4-chlorobenzoic acid (3.5 g, 12.4 mmol),4-dimethylaminopyridine (1.65 g, 13.5 mmol),1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (2.6 g, 13.5mmol) and benzoin (2.63 g, 12.4 mmol) in dichloromethane (20 mL) wasstirred at room temperature for 4 h. The reaction mixture was washedwith HCl (1N), NaOH (0.1 N), brine, dried over anhydrous MgSO₄ andconcentrated to give the crude ketoester (5.9 gm, 99%).

[0363] A mixture of ketoester (5.9 g, 12 mmol) and ammonium chloride(5.50 g, 71 mmol) in glacial acetic acid (45 mL) was stirred at refluxfor 4 hr. The reaction mixture was cooled and poured on ice. Thetar-like solid was digested with hot ethanol (25 mL). The resultingbeige solid was collected to give the title compound (4.5 g, 88%).

[0364] The experimental procedure as described in Example 37 Part B wasfollowed employing the above Part A compound to give the title compound(yield 92%).

[0365] The experimental procedure as described in Example 37 Part C wasfollowed, employing the above Part B compound, to give the titlecompound (yield 80%).

[0366] The Part C compound (0.48 g, 0.94 mmol) was diluted with ethanol(8 mL) and treated with NaOH (0.40 g; 10 mmol) and 3 mL of water. After18 h at RT the mixture was acidified with citric acid to pH 3. Themixture was diluted with equal volumes of ethyl acetate and water. Thelayers were equilibrated and the organic fraction dried (Na2SO4) andconcentrated. The residue was purified by preparative reverse phasecolumn chromatography. The isolated material was further purified byflash column chromatography on silica gel with gradient elution from 4%ethanol in dichloromethane to 10% ethanol in dichloromethane with atrace of acetic acid to give the title compound (90 mg, 20%).

EXAMPLE 43

[0367]

[0368] A mixture of cyclohexane carboxaldehyde (2.800 gm, 25 mmol) andtrimethylsilyl cyanide (2.475 gm,25 mmol) was treated with zinc iodide(2 mg, 0.006 mmol). The mixture was stirred at RT for 3 h. The titlecompound was used without further purification, yield 100%.

[0369] A mixture of Part A compound (2.00 g, 9.45 mmol) in THF (20 mL)at RT was treated with phenylmagnesiun chloride (3M in THF, 6.6 mL, 20mmol). The mixture was stirred for 1 h at RT and then heated to refluxfor 4 h. The reaction mixture was cooled and stirred with an excess of1N HCl solution for 18 h. The mixture was partitioned between ether andwater. The organics were dried over MgSO4, concentrated, and the residuepurified by flash column chromatography on silica gel eluting with astep gradient of 1:9 to 3:7 ethyl acetate/hexane to give the titlecompound (750 mg, 34%).

[0370] A solution of Example 40 Part A compound (330 mg, 1.0 mmol),4-dimethylamino pyridine (40 mg, 0.3 mmol),1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (230 mg, 1.2mmol) and Part B compound (220 mg, 1.0 mmol) in dichloromethane (2 mL)was stirred at room temperature for 4 h. The reaction mixture was washedwith water (2×50 mL), brine (50 mL), dried over anhydrous MgSO₄ andconcentrated. The residue was purified by flash column chromatography onsilica gel eluting with a step gradient of 5:95 to 10:90 ethylacetate/hexane to give title compound (400 mg, 75%).

[0371] A mixture of Part C compound (400 mg, 0.75 mmol) and ammoniumacetate (580 mg, 3.1 mmol) in glacial acetic acid (4 mL) was stirred atreflux for 18 h. The reaction mixture was cooled and concentrated. Thecrude oil was purified by flash column chromatography on silica geleluting with 3:97:0.5 methanol/dichloromethane/acetic acid to the givethe title compound (270 mg, 78%).

EXAMPLE 44

[0372]

[0373] A mixture of Example 43 Part A compound (2.11 g, 10 mmol) in THF(10 mL) at RT was treated with cyclohexylmagnesiun chloride (2M inether, 8 mL, 16 mmol). The mixture was stirred for 1 h at RT and thenheated to reflux for 3 h. The reaction mixture was cooled and stirredwith an excess of 1N HCl solution for 4 h. The mixture was partitionedbetween ether and water. The organics were dried over MgSO4,concentrated, and the residue purified by flash column chromatography onsilica gel eluting with a step gradient of 1:9 to 4:6 ethylacetate/hexane to give title compound as a foam (750 mg, 33%).

[0374] Part A compound was coupled with Example 40 Part A compoundemploying the procedure described in Example 43 Part C to obtain thetitle compound in 18% yeild.

[0375] A mixture of Part B compound (240 mg, 0.45 mmol) and ammoniumchloride (240 mg, 3.1 mmol) in glacial acetic acid (4 mL) was stirred atreflux for 24 h. The reaction mixture was cooled poured in water andfiltered. The crude beige solid was triturated with water to get thetitle compound (180 mg, 87%).

EXAMPLE 45

[0376]

[0377] A mixture of Example 5 Part A compound (0.75 g, 2 mmol) in 5 mLof DMF at RT was treated with K₂CO₃ (0.28 g, 2 mmol) and bromoethylacetate (1 mL, 6 mmol). The mixture was heated to 100° C. in a sealedtube stirred for 72 h. The mixture was cooled to RT and poured intowater. The organics were extracted with ethyl acetate, dried over Na₂SO₄and concentrated. The residue was purified on flash columnchromatography with 15:85 ethyl acetate/hexane to give the titlecompound (0.40 g, 46%).

[0378] Nitrogen was bubbled through a solution of Part A compound (300mg, 0.69 mmol), 3-aminophenyl boronic acid (158 mg, 1.00 mmol) andaqueous sodium carbonate (1 mL, 2M, 2 mmol) in toluene (2 mL) andethanol (1 mL) at room temperature for 15 min.Tetrakis(triphenylphosphine) palladium(0) (550 mg, 0.04 mmol) was addedand the mixture was stirred at 80° C. for 36 hr under argon. Thereaction mixture was cooled to room temperature and extracted with ethylacetate. The combined organic extracts were washed with brine, driedover anhydrous MgSO₄ and concentrated. The crude product was purified byflash chromatography on silica gel, eluting with 4:6 ethylacetate/hexane to give title compound (150 mg, 46%).

[0379] To a slurry of Part B compound (120 mg, 0.28 mmol) and potassiumcarbonate (40 mg, 0.28 mmol) in anhydrous dimethylformamide (3 mL) wasadded ethyl bromoacetate (50 mg, 0.28 mmol). The reaction mixture wasstirred at room temperature for 18 h. The reaction was partitionedbetween diethyl ether and aqueous sodium bicarbonate solution. Theorganic layer was washed with water, and brine, then dried overanhydrous MgSO₄ and concentrated. The crude product was purified byflash chromatography eluting with 3:7 ethyl acetate/hexane to give titlecompound (95 mg, 60%).

[0380] A mixture of Part C compound (90 mg, 0.16 mmol) in methanol (3mL) was treated with 1M NaOH solution (1 mL, 1 mmol). After stirring for3 h at reflux the mixture was cooled and diluted with ether. Citric acidwas added until the aqueous fraction maintained a pH of 3. The layerswere equilibrated and separated. The organic fraction was dried overMgSO₄, and concentrated to give the title compound (80 mg, 100%).

EXAMPLE 46

[0381]

[0382] A mixture of Example 40 Part B compound (0.59 g, 1.33 mmol) in 4mL of acetic acid with ammonium chloride (0.60 g, 7.8 mmol) was heatedto reflux for 48 h. The mixture was diluted with equal amounts of waterand ethyl acetate. The organic fraction was washed with water, dried(MgSO₄) and concetrated. The remainder was purified on silica by flashcolumn chromatography with 3:97:0.1 THF:dichloromethane:acetic acid togive 15 mg (3%) title compound.

EXAMPLE 47

[0383]

[0384] A mixture of Example 5 Part A compound (0.75 g, 2 mmol) in DMF (5mL) was treated with K2CO3 (420 mg, 4 mmol) and isobutyl iodide (740 mg,4 mmol). The mixture was heated in a sealed tube at 60° C. for 18 h. Thetube was cooled, and the contents diluted with equal amounts of waterand ether. The organic fraction was dried over anhydrous MgSO₄ andconcentrated to a thick oil. The crude product was purified by flashchromatography on silica gel, eluting with a step gradient of 2:98 to7:93 ethyl acetate/hexane to give title compound (250 mg, 30%).

[0385] The experimental procedure as set out in Example 37 Part Bemploying the above Part A compound was followed to give the titlecompound (yield 62%).

[0386] The experimental procedure as set out in Example 37 Part Cemploying the above Part B compound was followed to give the titlecompound (yield 72%).

[0387] The experimental procedure as set out in Example 37 Part Demploying the above Part C compound was followed to give the titlecompound (yield 61%).

EXAMPLE 48

[0388]

[0389] A solution of Example 6 Part A compound (0.49 g, 1.18 mmol) inDMF (2 mL) at RT was treated with K₂Co₃ (0.28 g, 2 mmol) andbromoacetonitirile (0.14 g; 1.20 mmol). The mixture was stirredovernight at RT and then heated to 60° C. for 4 h. The reaction mixturewas cooled to RT and poured into water. The solid was collected anddried overnight to give the title compound (0.45 g, 85%).

[0390] A solution of Part A compound (0.40 g, 0.88 mmol) in xylene (2mL) was treated with azidotrimethyltin (0.23 g, 1.14 mmol) and themixture was heated under N2 for 18 h at 135° C. The reaction wasquenched with methanol and the mixture concentrated to an oil. The oilwas purified by flash column chromatography on silica with a step wisegradient using 15/85 ethyl acetate/hexane then 5/95methanol/dichloromethane to give 0.30 g of the title compound as a whitefoam (68%).

EXAMPLE 49

[0391]

[0392] A mixture of Example 34 Part B compound (0.20 g, 0.64 mmol),pyridinium p-toluenesulfonate (40 mg), andmeso-1,2-dihydroxy-1,2-diphenylethane (0.14 g, 0.64 mmol) in toluene (5mL) was heated to 80° C. for 36 h and then brought to reflux for 3 h.The mixture was cooled to RT and diluted with water and ethyl acetate.The organics were dried (MgSO₄) and carried on to the next step withoutfurther characterization.

[0393] The crude ester (^(˜)0.64 mmol) in methanol (4 mL) was treatedwith 1M NaOH (1 mL, 1 mmol) and stirred overnight. The mixture wasconcentrated and the residue purified by chromatograpy on SP207 gel witha stepwise gradient from water to 80% methanol/water in 20% increments(70 mL portions). The pure fractions were combined and freeze dried togive the title compound as a white lyophilate (130 mg, 45%).

EXAMPLE 50

[0394]

[0395] A mixture of Example 34 Part B compound (0.20 g, 0.64 mmol),pyridinium p-toluenesulfonate (40 mg), and(R,R)-1,2-dihydroxy-1,2-diphenylethane (0.14 g, 0.64 mmol) in toluene (5mL) was heated to 80° C. for 36 h and then brought to reflux for 3 h.The mixture was cooled to RT and diluted with water and ethyl acetate.The organics were dried (MgSO₄) and carried on to the next step withoutfurther characterization.

[0396] The crude ester (^(˜)0.64 mmol) in methanol (4 mL) was treatedwith 1M NaOH (1 mL, 1 mmol) and stirred overnight. The mixture wasconcentrated and the residue purified by chromatograpy on SP207 gel witha stepwise gradient from water to 80% methanol/water in 20% increments(70 mL portions). The pure fractions were combined and freeze dried togive the title compound as a white lyophilate (200 mg, 65%).

EXAMPLE 51

[0397]

[0398] The experimental procedure as set out in Example 37 Part A usingtert-butyl bromoacetate as the alkylating agent was followed to give thetitle compound (yield 92%).

[0399] The experimental procedure as set out in Example 37 Part Bemploying the above Part A compound was followed to give the titlecompound (yield 76%).

[0400] The experimental procedure as set out in Example 37 Part Cemploying the above Part B compound was followed using tert-butylbromoacetate to give the title compound (yield 75%).

[0401] Part C compound (0.16 g, 0.26 mmol) in a 1:1 mixture oftrifluoroacetic acid/dichloromethane (4 mL) was stirred at roomtemperature overnight. The mixture was concentrated and the residueadjusted to pH 13 with 1N NaOH solution. The solution was purified bychromatograpy on SP207 gel with a stepwise gradient from water to 60%methanol/water in 20% increments (80 mL portions). The pure fractionswere combined, the pH of the combined fractions were adjusted to pH 6.5with 0.1 N NaOH and freeze dried to give 83 mg (62%) of title compoundas a white lyophilate.

EXAMPLE 52

[0402]

[0403] A mixture of Example 8 Part B compound (0.25 g, 0.6 mmol), K2CO3(0.12 g, 0.9 mmol) and DMF (3 mL) was treated with bromoacetonitrile(0.11 g; 0.9 mmol) and the mixture stirred for 72 h. TLC indicated thatthe reaction was not complete and additional bromoacetonitrile (0.11 g,0.9 mmol) and K2CO3 (0.12 g, 0.9 mmol) were added. The mixture wasstirred for 18 h. The mixture was diluted with equal amounts of ethylacetate and water. The organic fraction was washed with water, dried(MgSO4) and concentrated. The remainder was purified by flash columnchromatography with 20% ethyl acetate in hexane to give 0.22 g (80%) ofthe title compound.

[0404] A mixture of Part A compound (0.20 g, 0.44 mmol) in xylenes (2mL) was treated with azidotrimethyltin (0.11 g, 0.53 mmol) and warmed to135° C. (bath temp) for 18 h. The mixture was concentrated and stirredwith methanol for 45 min. The methanol solution was concentrated and theresidue purified by flash column chromatography with a step gradientelution using dichloromethane (80 mL), 1% methanol/dichloromethane (200mL) and 2% methanol/dichloromethane (200 mL) to give 36 mg (16%) of thetitle compound.

EXAMPLE 53

[0405]

[0406] A solution of 1,3-diphenyl-1,3-propanedione (4.50 g, 20 mmol) in150 mL of dichloromethane was mixed with triethylamine (2.07 g, 20 mmol)and cooled to −5° C. (internal temperature). The mixture was thentreated with 4-aetamidobenzenesulfonyl azide (4.80 g, 21 mmol). Thereaction was maintained at −4° C. for 4 h and then warmed to RTovernight. The mixture was diluted with water and the organic fractionwas washed with 1 N NaOH solution (4×125 mL), water (2×50 mL), dried(Na2SO4) and concentrated to an oil. The oil was diluted with a smallvolume (15 mL) of methanol and 3 drops of water. The resulting solid wascollected and dried to give 1.50 g (30%) of the title compound.

[0407] (Reference Meier, H. Chem Ber. 119, 3382-3393, 1986.)

[0408] A mixture of the Part A compound (1.5 g; 6 mmol) in 50 mL ofethanol was refluxed for 18 h. The ethanol was stripped off underreduced pressure to leave a thick oil. The oil was solidified by mixingwith hexane (10 mL) and concentrating under reduced pressure. Afterdrying 1.6 g (100%) of the title compound was obtained as a beige solid.

[0409] A mixture of Part B compound (0.1 g, 0.37 mmol) in 3 mL ofethanol was treated with 2-bromophenylhydrazine hydrochloride (84 mg,0.37 mmol) and heated to reflux overnight. The ethanol was removed andthe remainder was purified on silica gel by flash column chromatographywith 65:35 ethyl acetate:hexane to give 90 mg (62%) of the titlecompound.

[0410] A mixture of Part C compound (0.13 g, 0.33 mmol), K₂CO₃ (0.10 g,0.73 mmol) and DMF (3 mL) was treated with methyl iodide (0.10 g, 0.70mmol) and the mixture stirred for 18 h. The mixture was diluted withequal amounts of ethyl acetate and water. The organic fraction waswashed with water, dried (MgSO₄) and concentrated. The remainder waspurified by flash column chromatography with 10% ethyl acetate in hexaneto give 80 mg (60%) of the title compound.

[0411] A mixture of Part D compound (80 mg, 0.19 mmol), toluene (1 mL),ethanol (0.5 mL), 3-aminophenyl boronic acid (35 mg, 0.25 mmol), and 2 NNa2CO3 solution (0.125 μL, 0.25 mmol) was degassed with a gentle N2 flowfor 10 min. The mixture was treated withterakis(triphenylphosphine)-palladium (0) (10 mg) and the mixture heatedto 80° C. for 18 h. The mixture was cooled to RT and diluted with equalportions of water and ethyl acetate. The organic fraction was dried overMgSO₄ and concentrated. The remainder was purified on silica gel byflash column chromatography with 65:35 ethyl acetate:hexane as a mobilephase to give 66 mg (80%) of the title compound.

[0412] A mixture of DMF (0.5 mL), potassium carbonate (30 mg, 0.21 mmol)and Part E compound (60 mg, 0.15 mmol) was treated with ethylbromoacetate (17 μL, 0.15 mmol). The mixture was stirred overnight anddiluted with equal potions of ethyl acetate and water. The layers wereequilibrated, the organic fraction dried (MgSO₄) and concentrated. Theresidue was purified on silica gel by flash column chromatography with20:80 ethyl acetate:hexane as a mobile phase to give 60 mg (80%) of thetitle compound.

[0413] A solution of Part F compound (60 mg, 0.12 mmol) and methanol (3mL) was treated with 1 N NaOH solution (1 mL, 1 mmol) and stirredovernight. The mixture was acidified with citric acid until a pH of 3was maintained. The resulting slurry was diluted with equal portions ofethyl acetate and water and the layers equilibrated. The orgaincfraction was dried over Na₂ SO₄ and concentrated. Pumping overnight gave50 mg (88%) of the title compound.

EXAMPLE 54

[0414]

[0415] The title compound was generated by the procedure described inExample 19 starting/with Compound A Example 13.

EXAMPLE 55

[0416]

[0417] The title compound was generated following the proceduredescribed in Example 34 utilizing 4,4′-difluorobenzil.

EXAMPLE 56

[0418]

[0419] The title compound was generated from Example following theprocedure described in Example 35.

EXAMPLE 57

[0420]

[0421] Following the procedure described in Example 35, Compound AExample 35 was alkylated with chloromethyl methyl ether and hydrolyzedto give the title compound.

EXAMPLE 58

[0422]

[0423] Following the procedure described in Example 35, Compound AExample 35 was alkylated with 1-bromo-2-fluoroethane and hydrolyzed togive the title compound.

EXAMPLE 59

[0424]

[0425] The title compound was generated by the procedure described inExample 8 starting with Example 19 Part E compound.

EXAMPLE 60

[0426]

[0427] The title compound was generated following the proceduredescribed in Example 23, starting with Example 21 Part A compound.

EXAMPLE 61

[0428]

[0429] To a stirred solution of 2-bromobenzoyl chloride (1.31 mL, 10.0mmol) in THF (10 mL) under argon at −22° C. was added tributylphosphine(2.74 mL, 11.0 mmol) over 10 min. The temperature was not allowed torise above −15° C. After 20 min, a solution of n-propylmagnesiumchloride (5.0 mL, 10.0 mmol, 2 M in ether) was added in one portion. Thereaction temperature rose almost at once to 34° C. and subsided to −20°C. over 10 min. After an additional 10 min, 1 M aqueous HCl (18 mL) wasadded and the mixture was extracted with ether (100 mL). The etherextract was washed once with brine, once with saturated sodiumbicarbonate solution, dried (MgSO₄) and evaporated. Purification byflash chromatography on silica gel (5×25 cm column, 38:62CH₂Cl₂/hexanes) gave the title compound as a yellow oil, 2.28 g, 100%yield.

[0430] To a stirred solution of potassium hydroxide (1.23 g, 22 mmol) inmethanol (10 mL) at room temperature under argon was added Part Acompound (1.00 g, 4.40 mmol). After five min, benzaldehyde (1.34 mL,13.2 mmol) was added in one portion. After 4 h, the reaction mixture wascooled to 0° C., treated with 1 M aqueous HCl to bring the solution topH 7.5 and then evaporated at <30° C. The residue was partitionedbetween CH₂Cl₂ and brine. The aqueous phase was extracted twice withCH₂Cl₂, and the extracts were combined, dried (MgSO₄) and evaporated.Purification by flash chromatography on silica gel (5×15 cm column, 2:3CH₂Cl₂/hexanes) gave the title compound as a light yellow oil, 1.29 g,95% yield.

[0431] To a stirred slurry of benzaldehyde (5.1 mL, 50.0 mmol),potassium cyanide (13 g, 200 mmol), and t-butyldimethylsilyl chloride(9.0 g, 60 mmol) in acetonitrile (100 mL) at room temperature underargon was added zinc iodide (250 mg, 0.8 mmol). After 14 h, the reactionmixture was filtered and the filtrate evaporated. The evaporate wasslurried in hexanes for 1 h under nitrogen, refiltered and evaporated.The oily residue was distilled (80-83° C., 0.8 torr) to give the titlecompound as a colorless oil, 7.68 g, 62% yield.

[0432] A solution of lithium diisopropylamide was prepared at 0° C.under argon from diisopropylamine (1.2 mL, 8.1 mmol) and n-butyllithium(3.2 mL, 8.0 mmol, 2.5 M in hexanes) in ether (20 mL). To this solutionat −72° C. was added a solution of Part C compound (1.80 g, 7.30 mmol)in ether (5 mL). The temperature was not allowed to rise above −67° C.After 1 h, a solution of Part B compound (2.30 g, 7.30 mmol) was addedover the course of 10 min. The reaction was stirred at −78° C. for 2 hand then stored at −40° C. for 14 h. The reaction was then warmed to 0°C. for 30 min and then quenched with saturated ammonium chloridesolution. The reaction mixture was extracted with ether (100 mL). Theextract was dried (MgSO₄) and evaporated. Purification by flashchromatography on silica gel (5×25 cm column, 1:1 CH₂Cl₂/hexanes) gavethe title compound as a white amorphous solid, 1.88 g, 46% yield.

[0433] To a solution of Part D compound (1.65 g, 2.93 mmol) in THF (5mL) at room temperature under argon was added tetrabutylammoniumfluoride solution (3.6 mL, 3.6 mmol, 1 M in THF). After 1 h, thereaction was quenched with saturated sodium bicarbonate solution andextracted twice with CH₂Cl₂ (50 mL). The extracts were combined, dried(MgSO₄) and evaporated. Purification by flash chromatography on silicagel (5×25 cm column, 1:1 CH₂Cl₂/hexanes) gave the title compound (as amixture of diastereomers) as a colorless oil, 1.05 g, 85% yield.

[0434] Analogous to the procedure described in Example 19 Part C,Compound E (600 mg, 1.42 mmol) gave the title compound as a colorlessoil, 557 mg, 97% yield.

[0435] Analogous to the procedures described in Example 8, Part Fcompound gave the title compound.

EXAMPLE 62

[0436]

[0437] Analogous to the procedure described in Example 19, Example 21Part A compound gave the title compound.

EXAMPLE 63

[0438]

[0439] Analogous to the procedure described in Example 8, Example 21Part A compound gave the title compound

EXAMPLE 64

[0440]

[0441] Analogous to the procedure described in Example 8, Example 20Part A compound gave the title compound

EXAMPLE 65

[0442]

[0443] Analogous to the procedure described in Example 23, Example 61Part F compound gave the title compound.

EXAMPLE 66

[0444]

[0445] To a stirred slurry of NaH (60% oil dispersion, 10.0 g, 250 mmol)in diethyl carbonate (40 mL) and toluene (15 mL) at room temperatureunder argon, was added absolute ethanol (150 μL) and then a solution of2-bromoacetophenone (24.88 g, 125 mmol) in toluene (20 mL) over 20 min.The reaction temperature rose autogenously to 80° C. and then wasmaintained at that temperature for 2 h. The mixture was cooled to roomtemperature and acetic acid (15 mL) was added. The resulting bulky solidwas treated with ice-cold water (100 mL) and then extraced twice withether (250 mL). The extracts were combined, dried (MgSO₄) and evaporatedto give the crude ketoester as a yellow oil, 29.75 g. Purification of aportion of the crude product (log) by flash chromatography on silica gel(5×25 cm column, 9:1 CH₂Cl₂/hexanes) gave the title compound as a lightyellow oil, 7.83 g, 70% calculated yield.

[0446] A solution of Part A compound (5.42 g, 20.0 mmol), benzaldehyde(2.24 mL, 22 mmol), 6-aminocaproic acid (100 mg, 0.76 mmol) and aceticacid (3 mL) in benzene (10 mL) was heated to reflux for 1 h using aDean-Stark trap. The reaction mixture was cooled to room temperature,diluted with ethyl acetate and washed four times with saturated sodiumbicarbonate solution until the washings were pH 8. The organic phase wasdried (MgSO₄) and evaporated. Purification of the crude product by flashchromatography on silica gel (5×25 cm column, 7:3 CH₂Cl₂/hexanes) gavethe title compound (55:45 mixture of geometric isomers) as a whiteamorphous solid, 4.38 g, 61% yield.

[0447] Analogous to the procedure described in Example 19 Part B, Part Bcompound was used to prepare the title compound.

[0448] Analogous to the procedure described in Example 19 Part C, Part Ccompound was used to prepare the title compound.

[0449] Analogous to the procedure described in Example 8 Part A, Part Dcompound was used to prepare the title compound.

[0450] Analogous to the procedure described in Example 8 Part B, Part Ecompound was used to prepare the title compound.

[0451] To a stirred solution of Example 66 Part F compound (497 mg, 1.08mmol) in THF (2 mL) at room temperature under argon was added a solutionof lithium aluminum hydride (1.5 mL, 1.5 mmol, 1 M in THF) over 30 sec.The resulting light yellow solution was stirred for 15 min, whereupon agelatinous mixture formed. This was quenched cautiously with 5%potassium hydrogen sulfate solution and extracted three times with ethylacetate (20 mL). The organic extracts were combined, dried (MgSO₄) andevaporated to give a light pink solid, 440 mg, 97% yield.

[0452] Analogous to the procedure described in Example 8 Part C, Part Gcompound was used to prepare the title compound.

[0453] By the procedure described in Example 8 Part D, Part H compoundwas used to prepare the title compound.

EXAMPLE 67

[0454]

[0455] To a stirred solution of Example 66 Part H compound (112 mg,0.222 mmol) in methanol (5 mL) was added concentrated sulfuric acid (2drops). The mixture was heated in a sealed tube at 100° C. for 9 h. Thereaction mixture was cooled to room temperature, treated with saturatedsodium bicarbonate solution and evaporated to dryness. The residue wasdissolved in CH₂Cl₂, dried (MgSO₄) and evaporated to give the title.compound as a colorless oil, 98 mg, 88% yield.

[0456] Analogous to the procedure described in Example 8 Part D, Part Acompound was used to prepare the title compound.

EXAMPLE 68

[0457]

[0458] By the procedure described in Example 67, Example 66 Part Hcompound was used to prepare the title compound, substituting ethanolfor methanol in the procedure.

EXAMPLE 69

[0459]

[0460] Analogous to the procedure described in Example 20, Example 61Part E compound was used to prepare the title compound.

[0461] Analogous to the procedure described in Example 8, Example 69Part A compound was used to prepare the title compound.

EXAMPLE 70

[0462]

[0463] A steady stream of dried air was bubbled into a stirred slurryconsisting of Example 66 Part H compound (504 mg, 1.0 mmol), powdered 4A molecular sieves (200 mg) and tetrapropylammonium perruthenate (30 mg,0.085 mmol) in toluene (3.5 mL) as the reaction was heated to 65° C.After 1 h, the reaction was cooled to room temperature, diluted withCH₂Cl₂ and filtered through silica gel (˜20 g). Evaporation gave thetitle compound as a colorless oil, 490 mg, 97%).

[0464] To a solution of Part A compound (125 mg, 0.25 mmol) in CH₂Cl₂ atroom temperature under argon, was added a solution of trimethylaluminum(0.25 mmol, 0.5 mmol, 2 M in CH₂Cl₂), dropwise over 5 min. After 1 h,the reaction was quenched cautiously with 10% citric acid solution andextracted once with CH₂Cl₂. The organic phase was dried (MgSO₄) andevaporated. Purification of the crude product by flash chromatography onsilica gel (2.5×15 cm column, 3:97 ether/CH₂Cl₂) gave the title compoundas a colorless oil, 124 mg, 96% yield.

[0465] Analogous to the procedure described in Example 8 Part D, Part Bcompound was hydrolyzed to prepare the title compound.

EXAMPLE 71

[0466]

[0467] Analogous to the procedure described in Example 23, Example 69Part A compound was used to prepare the title compound.

EXAMPLE 72

[0468]

[0469] Analogous to the procedure described in Example 3, Example 61Part F compound was used to prepare the title compound.

EXAMPLE 73

[0470]

[0471] To a stirred slurry of 2-bromophenylhydrazine hydrochloride(31.02 g, 0.139 mol) at room temperature under nitrogen in 95% ethanol(500 mL) was added sodium acetate trihydrate (18.87 g, 0.139 mol) anddeoxybenzoin (30.96 g, 0.139 mol). The mixture was heated to reflux for2 h and then partially cooled and evaporated. The residue was slurriedin saturated sodium bicarbonate solution (300 mL), filtered, washed withwater and dried in vacuo at 60° C. for 16 h. The resulting solids weretriturated in hot methanol (200 mL), filtered and dried to provide thetitle compound (96:4 mixture of Z/E isomers) as a white solid, mp126-128° C., 36.84 g, 76% yield.

[0472] To a stirred slurry of sodium hydride (60% dispersion, 1.43 g,35.8 mmol) in N-methylpyrrolidone (NMP, 25 mL) at room temperature undernitrogen, was added a solution of Part A compound (10.0 g, 27.4 mmol) inNMP (15 mL) over 5 min. The temperature autogenously rose to 54° C. asgas was evolved and a deep red solution formed. The reaction mixture washeated to 60° C. for 3 h and then cooled to room temperature. To thissolution was added freshly distilled propionic anhydride (4.6 mL, 35.9mmol) at a rate to keep the reaction temperature below 35° C. Thereaction mixture was stirred 2 h, then quenched with 5% potassiumhydrogen sulfate solution and extracted four times with ether (100 mL).The ether extracts were combined, washed twice with water, once withbrine, dried (MgSO₄) and evaporated to give an orange oil, 12.9 g.Purification of the crude product by flash chromatography on silica gel(12×30 cm column, 1:4 ethyl acetate/hexanes) gave the title compound asa light yellow oil, 8.15 g, 71% yield.

[0473] To a solution of Part B compound (2.33 g, 5.53 mmol) in DMF (15mL) at room temperature under nitrogen was added sodium hydride (60%dispersion, 550 mg, 13.8 mmol) in several portions over 1 min. Thereaction warmed autogenously to 38° C. and was further heated to 50° C.for 20 min. The deep red reaction mixture was cooled in a water ice bathand quenched by adding 5% potassium hydrogen sulfate solution (10 mL)dropwise over 10 min. The mixture was then acidified with 1 Nhydrochloric acid to bring the mixture to pH 2 and then extracted threetimes with ether (50 mL). The combined organic extracts were washedtwice with water and once with brine, dried (MgSO₄) and evaporated.Purification of the crude product by flash chromatography on silica gel(5×25 cm column, 1:3 ethyl acetate/hexanes) gave the title compound as alight yellow amorphous solid, 1.63 g, 73% yield.

[0474] The title compound was generated by the procedure described inExample 8 starting with Compound C Example 73.

EXAMPLE 74

[0475]

[0476] The title compound was generated by the procedure described inExample 23 starting with Example 73 Part C compound.

EXAMPLE 75

[0477]

[0478] The title compound was generated by the procedure described inExample 3 starting with Example 73 Part C compound.

EXAMPLE 76

[0479]

[0480] A stirred slurry of sodium hydride (60% dispersion, 1.64 g, 41.1mmol) in N-methylpyrrolidone (NMP, 13 mL) at room temperature undernitrogen, was heated to 40° C. for 30 min. To this mixture was addedExample 73 Part A compound (5.00 g, 13.7 mmol) in NMP (30 mL) in oneportion. The reaction mixture was heated to 60° C. for 4 h and thencooled to room temperature. To this solution was added freshly distilledacetyl chloride (4.3 mL, 57.5 mmol) in NMP (5 mL) at a rate to keep thereaction temperature below 50° C. The reaction mixture was stirred 30min, then quenched with water (300 mL), extracted twice with ether (100mL) and twice with ethyl acetate. The organic extracts were combined,washed with saturated sodium bicarbonate solution, water, and brine,dried (MgSO₄) and evaporated. Purification of the crude product by flashchromatography on silica gel (5×20 cm column, 1:2 hexanes/CH₂Cl₂) gavethe title compound as a white amorphous solid, 1.20 g, 23% yield.

[0481] The title compound was generated by the procedure described inExample 8 starting with Part A compound.

EXAMPLE 77

[0482]

[0483] The title compound was generated by the procedure described inExample 23 starting with Example 76 Part A compound.

EXAMPLE 78

[0484]

[0485] A mixture of 2-bromoaniline (2.18 g, 12.7 mmol) and2,3-diphenylmaleic anhydride (3.17 g, (12.7 mmol) were stirred andheated under argon to 200° C. for 6 h. The mixture was cooled to roomtemperature, dissolved in CH₂Cl₂ (50 mL), dried (MgSO₄) and evaporated.Purification of the crude product by flash chromatography on silica gel(5×25 cm column, 2 L of 3:7 hexanes/CH₂Cl₂, then CH₂Cl₂) gave first4-(2-bromoanilino)-2,3-diphenyl-4-hydroxybutyrolactone (2.16 g, 40%yield) as a yellow solid, mp 162-164° C. and then the title compound asa bright yellow solid, mp 178-180° C., 2.00 g, 39% yield.

[0486] The title compound was generated by the procedure described inExample 8 starting with Example 78 Part A compound.

EXAMPLE 79

[0487]

[0488] Analogous to the procedure described in Example 23 Part A,Example 73 Part C compound was used to prepare the title compound.

[0489] To a stirred solution of triethylphosphonoacetate (0.50 mL, 2.5mmol) in THF (2.5 mL) under nitrogen at room temperature was addedsodium hydride (60% dispersion, 100 mg, 2.5 mmol). After 10 min, thereaction was heated to 50° C. After an additional 20 min, a solution ofExample 73 Part C compound (775 mg, 1.80 mmol) in THF (2 mL) was addedas one portion. The reaction mixture was stirred for 2 h, cooled to roomtemperature and partitioned between ethyl acetate (50 mL) and 5%potassium hydrogen sulfate solution. The organic phase was dried (MgSO₄)and evaporated. Purification of the crude product by flashchromatography on silica gel (5×15 cm column, 1:49 ether/CH₂Cl₂) gavethe title compound as a colorless oil, 785 mg, 88% yield.

[0490] Analogous to the procedure described in Example 8 Part D, Part Bcompound was used to prepare the title compound.

EXAMPLE 80

[0491]

[0492] Hydrogenation of Example 79 Part B compound (765 mg, 1.53 mmol)was performed at room temperature and atmospheric pressure in ethanol(10 mL) using 10% palladium/charcoal (100 mg). After 4 h, the reactionmixture was purged with nitrogen, filtered (0.45 p nylon filter) and thefiltrate evaporated to provide the title compound as a colorless oil,770 mg, 100% yield.

[0493] Analogous to the procedure described in Example 8 Part D, Part Acompound was used to prepare the title compound.

EXAMPLE 81

[0494]

[0495] The title compound was generated in analogy to the proceduresdescribed in Examples 5, 9, and 11.

EXAMPLE 82

[0496]

[0497] The title compound was generated in analogy to the proceduresdescribed in Examples 5 and 6.

EXAMPLE 83

[0498]

[0499] In analogy to the procedure described in Example 15, oxidation ofExample 5 Part C compound afforded the title compound.

EXAMPLE 84

[0500]

[0501] A mixture of Example 53 Part C compound (50 mg, 0.13 mmol), K₂CO₃(26 mg, 0.19 mmol) and DMF (3 mL) was treated with ethyl iodide (60 mg,0.38 mmol) and the mixture stirred for 18 h. The mixture was dilutedwith equal amounts of ethyl acetate and water. The organic fraction waswashed with water, dried (MgSO₄) and concentrated. The remainder waspurified by flash column chromatography with 20% ethyl acetate in hexaneto give 48 mg (94%) of the title compound.

[0502] The experimental procedure as described in Example 53 Part E wasfollowed for Suzuki coupling between the above Part A compound and3-aminophenyl boronic acid to give the title compound (yield 91%).

[0503] The experimental procedure as set out in Example 53 Part F wasfollowed employing the above Part B compound to give the title compound(yield 68%).

[0504] The experimental procedure as set out in Example 53 Part G wasfollowed employing the above Part C compound to give the title compound(yield 92%).

[0505] The molecular weight and mass spectral analysis of each of thecompounds prepared in Examples 1 to 84 are set out in the followingtables. TABLE 1 Linker variations in the oxazole series

MS observed Ex. X Z MW (M + H)⁺ 13 —OCH(Me)— CO₂H 461.52 462 54 —OCH₂—tetrazole 471.52 472 16 —CH═CH— CO₂H 443.51 441 17 —CH₂CH₂— CO₂H 445.52446 3 —NHCH₂— CO₂H 446.51 447 4 —NHCO— CO₂H 460.49 461 18 cyclopropylCO₂H 457.53 458 25 —N(Me)CH₂— CO₂H 460.54 461 15 bond CO₂H 417.47 418 14—CH₂— CO₂H 431.5 432 2 bond tetrazole 441.5 442 1 —CH₂— tetrazole 455.52456

[0506] TABLE 2 Ring substitution

Ex. HET R¹ R² R³ R⁴ 26 A phenyl phenyl 3-Me H 27 A phenyl phenyl H 4′-Me24 A phenyl phenyl 3-Me H 42 A phenyl phenyl 4-Cl H 41 A 2-pyridyl2-pyridyl H H 44 A c-C₆H₁₁ c-C₆H₁₁ H H 40 A H phenyl H H 43 A c-C₆H₁₁phenyl H H 46 B Ph H H H 55 B 4-F—Ph 4-F—Ph H H 56 C 4-F—Ph 4-F—Ph H HMS observed Ex. X-A MW (M + H)⁺ 26 —NHCH₂CO₂H 460.54 461 27 —NHCH₂CO₂H460.54 461 24 —OCH₂CO₂H 461.52 462 42 —NHCH₂CO₂H 480.96 481 41 —OCH₂CO₂H449.47 449 (M)⁺ 44 —OCH₂CO₂H 459.59 460 40 —OCH₂CO₂H 371.4  372 43—OCH₂CO₂H 453.54 454 46 —OCH₂CO₂H 370.41 371 55 —OCH₂CO₂H 482.49 483 56—OCH₂CO₂H 510.54 511

[0507] TABLE 3 X-Z variation at the ortho position

MS observed Ex. X Z MW (M + H)⁺ 31 —CH═CH— CO₂H 443.51 444 32 —CH₂CH₂—CO₂H 445.5 446 33 bond CO₂H 417.47 418 12 bond tetrazole 441.5 442

[0508] TABLE 4 Imidazole based analogs

MS observed Ex. R⁸ X Z MW (M + H)⁺ 36 Me —OCH₂— CO₂H 460.54 461 38 H—NHCH₂— CO₂H 445.53 446 39 Me —NHCH₂— CO₂H 459.55 460 6 Et —NHCH₂— CO₂H473.58 474 37 Propyl —NHCH₂— CO₂H 487.61 488 45 —CH₂CH₂OH —NHCH₂— CO₂H489.58 490 9 Et —CH═CH— CO₂H 470.58 471 47 —CH₂CH(Me)₂ —NHCH₂— CO₂H501.63 502 48 Et —NHCH₂— tetrazole 497.61 498 11 Et —CH₂CH₂— CO₂H 472.59473 7 Et bond tetrazole 468.57 469 8 Et —OCH₂— CO₂H 474.56 475 51CH₂CO₂H —NHCH₂— CO₂H 503.56 504 5 Et —CH₂— tetrazole 482.59 483 10 Et—CH₂— CO₂H 458.57 459 83 Et bond CO₂H 444.54 445 52 Et —OCH₂— tetrazole498.59 499 34 H —OCH₂— CO₂H 446.51 447 35 allyl —OCH₂— CO₂H 486.58 48757 —CH₂OMe —OCH₂— CO₂H 490.56 491 58 —CH₂CH₂F —OCH₂— CO₂H 492.55 493 81—CH₂CH₂F —NHCH₂— CO₂H 491.57 492 82 —CH₂CH₂F —CH₂CH₂— CO₂H 490.58 491

[0509] TABLE 5 Furan, thiophene, and pyrrole derivatives

MS ob- served (M + Ex. W R⁹ X Z MW H)⁺ 23 O H —CH₂— tetra- 454.54 455zole 21 N—Et H —NHCH₂— tetra- 496.62 497 zole 22 S H —NHCH₂— CO₂H 461.59462 20 NH H —CH2— tetra- 453.55 454 zole 19 O H —OCH₂— tetra- 470.54 471zole 59 O H —OCH₂— CO₂H 446.51 447 60 N—Et H —CH₂— tetra- 481.61 482zole 61 O Et —OCH₂— CO₂H 474.56 475 62 N—Et H —OCH₂— tetra- 497.6  498zole 63 N—Et H —OCH₂— CO₂H 473.58 474 64 NH H —OCH₂— CO₂H 445.52 446 65O Et —CH₂— tetra- 482.59 483 zole 66 O —CH₂OH —OCH₂— CO₂H 476.53 477 68O —CH₂OEt —OCH₂— CO₂H 504.59 505 69 NH Et —OCH₂— CO₂H 473.58 474 70 O—CH(OH)Me —OCH₂— CO₂H 490.56 491 67 O —CH₂OMe —OCH₂— CO₂H 490.56 491 71NH Et —CH₂— tetra- 481.61 482 zole 72 O Et —NHCH₂— CO₂H 473.58 474

[0510] TABLE 6 Pyrazole based analogs

MS observed Ex. R⁹ X Z MW (M + H)⁺ 73 Et —OCH₂— CO₂H 474.56 475 74 Et—CH₂— tetrazole 482.59 483 84 OEt —NHCH₂— CO₂H 489.58 490 75 Et —NHCH₂—CO₂H 473.58 474 76 Me —OCH₂— CO₂H 460.54 461 77 Me —CH₂— tetrazole468.57 469 80 Et —CH₂CH₂— CO₂H 472.59 473 79 Et —CH═CH— CO₂H 470.58 471

[0511] TABLE 7 Various heterocyclic based analogs

MS observed Ex. Het X-Z MW (M + H)⁺ 49

—OCH₂CO₂H 452.51 475 (M + Na)⁺ 50

—OCH₂CO₂H 452.51 475 (M + Na)⁺ 28

—OCH₂CO₂H 476.54 477 30

—OCH₂CO₂H 463.5  464 29

—NHCH₂CO₂H 462.51 463 78

—OCH₂CO₂H 475.51 476 53

—NHCH₂CO₂H 475.55 476

EXAMPLE 85

[0512]

[0513] A mixture of 4-methoxy-benzonitrile (1.33 g, 10.0 mmol) and THFat −78° C. was treated with benzylmagnesium chloride in THF (5.1 mL,10.2 mmol) over 5 min. The mixture was warmed to 45° C. for 2 h andcooled to ice bath temperature. The mixture was then treated slowly with5 mL of 3N HCl and stirred for 2 h. Extraction with ethyl acetate (3×30mL) drying (MgSO4) and concentrating gave a yellow oil. The oil waspurified by flash column chromatography on silica gel with 4:6hexane:dichloromethane to give 1.54 g (68%) of the title compound as alight yellow solid.

[0514] Analogous to the procedure described in Example 73 Part A, Part Acompound and potassium acetate were used to prepare the title compoundin 82% yield.

[0515] To a stirred solution of Part B compound (1.00 g, 2.53 mmol) inN-methylpyrrolidone (NMP, 2 mL), 4-dimethylamino-pyridine (DMAP, 0.31 g,2.53 mmol), and N,N′-diisopropylethylamine (0.89 mL, 5.10 mmol) wasadded freshly distilled propionic anhydride (0.64 mL, 5.10 mmol) and thereaction heated to 90° C. for 2 h. The mixture was then treated every 24h for 72 h with three additional amounts of DMAP (0.31 g, 2.53 mmol),N,N′-diisopropylethylamine (0.89 mL, 5.10 mmol) and propionic anhydride(0.64 mL, 5.10 mmol). After the final addition the mixture was stirredovernight at 90° C. and cooled toroom temperature. The mixture wasdiluted with equal portions (50 mL) of 4N HCl and ethyl acetate andequilibrated. The organic fraction was washed with brine, saturatedNHCO₃ and brine, dried (MgSO₄) and concentrated to give 1.49 g of thetitle compound as a crude brown oil.

[0516] Analogous to the procedure described in Example 73 Part C, Part Ccompound was used to prepare the title compound in 50% yield.

[0517] A solution of Part D compound (1.00 g, 2.3 mmol) andtris(dibenzylidene acetone)dipalladium(0) (0.13 g, 0.14 mmol) in amixture of 1:3:1 THF:DME:water (10 mL) was treated with3-hydroxyphenylboronic acid (0.45 g, 3.24 mmol) followed by the additionof aqueous Na₂CO₃ (6.4 mL, 1.5 M, 9.63 mmol). The mixture was heated to50° C. for 2 h, cooled to room temperature and acidified to pH=3 with 2NHCl. The mixture was diluted with equal portions of ethyl acetate andbrine (50 mL) and equilibrated. The organic fraction was washed withbrine and 1N HCl, dried over Na₂SO₄ and concentrated to a solid. Thesolid was recrystallized from hot ethyl acetate to give 700 mg (68%) ofthe title compound.

[0518] A slurry of Part E compound (0.70 g, 1.57 mmol) in DMF (6 mL) wastreated with t-butyl bromoacetate (0.25 mL, 1.72 mmol) and cesiumcarbonate (0.51 g, 1.57 mmol) and stirred for 18 h. The reaction mixturewas partitioned between ethyl acetate and water. The organic layer waswashed with water, and brine, dried over MgSO₄ and concentrated. Thecrude product was purified by flash column chromatography on silica gelwith 3:7 ethyl acetate/hexane to give the title compound as a whitesolid (0.70 g, 80%).

[0519] To a solution of Part F compound (0.33 g, 0.6 mmol) in drydichloromethane (2 mL) at 0° C. was added boron tribromide indichloromethane (1M, 2.7 mL, 2.7 mmol). The solution was stirred at 0°C. for 3 h and at room temperature overnight. The mixture was dilutedwith water followed by 1N HCl and extracted with ethyl acetate. Thecombined organic extracts were washed with brine, dried over MgSO4 andconcentrated. The crude product was purified by preparative reversephase chromatography to give the title compound as a white solid (0.05g, 15%) and Example 86 part A compound (0.18 g, 55%). MS (titlecompound) [M+H]=505.

EXAMPLE 86

[0520]

[0521] Following the procedure in Example 85 Part F afforded the titlecompound (yield 55%).

[0522] Following the procedure as in Example 28 Part G, alkylation ofPart A compound with ethyl bromoacetate and cesium carbonate affordedthe title compound (15%).

[0523] Following the experimental procedure as in Example 28 Part H,hydrolysis of Part B compound afforded the title compound as a whitesolid (85%). MS [M+H]=491.

What is claimed is:
 1. A compound having the structure

wherein R¹ and R² are the same or different and are independentlyselected from hydrogen, alkyl, cycloalkyl, cycloalkenyl, aryl,heteroaryl, heteroarylalkyl, aralkyl, cycloheteroalkyl orcycloheteroalkylalkyl; R³ is selected from hydrogen, halogen, alkyl,alkenyl, alkynyl, alkoxy, cycloalkyl, cycloalkylalkyl, cycloalkenyl,alkylcarbonyl, cycloheteroalkyl, cycloheteroalkylalkyl,cycloalkenylalkyl, haloalkyl, polyhaloalkyl, cyano, nitro, hydroxy,amino, alkanoyl, alkylthio, alkylsulfonyl, alkoxycarbonyl,alkylaminocarbonyl, alkylcarbonylamino, alkylcarbonyloxy,alkylaminosulfonyl, alkylamino, dialkylamino, all optionally substitutedthrough available carbon atoms with 1, 2, 3, 4 or 5 groups selected fromhydrogen, halo, alkyl, polyhaloalkyl, alkoxy, haloalkoxy,polyhaloalkoxy, alkoxycarbonyl, alkenyl, alkynyl, cycloalkyl,cycloalkylalkyl, cycloheteroalkyl, cycloheteroalkylalkyl, hydroxy,hydroxyalkyl, nitro, cyano, amino, substituted amino, alkylamino,dialkylamino, thiol, alkylthio, alkylcarbonyl, acyl, alkoxycarbonyl,aminocarbonyl, alkynylaminocarbonyl, alkylaminocarbonyl,alkenylaminocarbonyl, alkylcarbonyloxy, alkylcarbonylamino,arylcarbonylamino, alkoxycarbonylamino, alkylsulfonyl, aminosulfinyl,aminosulfonyl, alkylsulfinyl, sulfonamido or sulfonyl; R⁴ is selectedfrom hydrogen, halogen, alkyl, alkenyl, alkynyl, alkoxy, aryl,heteroaryl, arylalkyl, heteroarylalkyl, arylalkenyl, arylalkynyl,cycloalkyl, cycloalkylalkyl, polycycloalkyl, polycycloalkylalkyl,cycloalkenyl, cycloalkynyl, alkylcarbonyl, arylcarbonyl,cycloheteroalkyl, cycloheteroalkylalkyl, cycloalkenylalkyl,polycycloalkenyl, polycycloalkenylalkyl, polycycloalkynyl,polycycloalkynylalkyl, haloalkyl, polyhaloalkyl, cyano, nitro, hydroxy,amino, alkanoyl, aroyl, alkylsulfonyl, arylsulfonyl, alkoxycarbonyl,aryloxycarbonyl, alkylaminocarbonyl, arylaminocarbonyl,alkylcarbonylamino, alkoxycarbonyloxy, alkylaminosulfonyl,arylaminosulfonyl, alkylamino, dialkylamino, all optionally substitutedthrough available carbon atoms with 1, 2, 3, 4 or 5 groups selected fromhydrogen, halo, alkyl, haloalkyl, polyhaloalkyl, alkoxy, haloalkoxy,polyhaloalkoxy, alkoxycarbonyl, alkenyl, alkynyl, cycloalkyl,cycloalkylalkyl, cycloheteroalkyl, cycloheteroalkylalkyl, aryl,heteroaryl, arylalkyl, arylcycloalkyl, arylalkenyl, arylalkynyl,aryloxy, aryloxyalkyl, arylalkoxy, arylazo, heteroaryloxo,heteroarylalkyl, heteroarylalkenyl, heteroaryloxy, hydroxy,hydroxyalkyl, nitro, cyano, amino, substituted amino, alkylamino,dialkylamino, thiol, alkylthio, arylthio, heteroarylthio, arylthioalkyl,alkylcarbonyl, arylcarbonyl, acyl, arylaminocarbonyl, alkoxycarbonyl,aminocarbonyl, alkynylaminocarbonyl, alkylaminocarbonyl,alkenylaminocarbonyl, alkylcarbonyloxy, arylcarbonyloxy,alkylcarbonylamino, arylcarbonylamino, alkoxycarbonylamino,arylsulfinyl, arylsulfinylalkyl, arylsulfonyl, alkylsulfonyl,aminosulfinyl, aminosulfonyl, arylsulfonylamino,heteroarylcarbonylamino, heteroarylsulfinyl, heteroarylthio,heteroarylsulfonyl, alkylsulfinyl, sulfonamido or sulfonyl; X is a bondor a linker group selected from (CH₂)_(n), O(CH₂)_(n), S(CH₂)_(n),cycloalkylene, N(R⁵) (CH₂)_(n), NHCO, or CH═CH where n=0-5 and R⁵ ishydrogen, alkyl, or alkanoyl; Z is CO₂H or tetrazole of the formula

or its tautomer; and the group

represents a heteroaryl group or cycloheteroalkyl group which mayfurther be optionally substituted with one or two groups, which may bethe same or different and are independently selected from alkyl,alkenyl, hydroxyalkyl, keto, carboxyalkyl, carboxy, cycloalkyl, alkoxy,formyl, alkanoyl, alkoxyalkyl or alkoxycarbonyl, including allstereoisomers thereof; and a pharmaceutically acceptable salt thereof,or a prodrug ester thereof; with the provisos that (1) n≠o when Z isCO₂H and X is O(CH₂)_(n), S(CH₂)_(n) or N(R⁵) (CH₂)_(n)); and (2) when

then X-Z may not be O-lower alkylene-CO₂H or —O-lower alkylene-CO₂alkylwhen R¹ and R² are both aryl or substituted aryl and R³ and R⁴ are eachhydrogen.
 2. The compound as defined in claim 1 wherein R³ and R⁴ arethe same or different and are independently selected from hydrogen,halogen, alkyl, alkoxy, alkylthio, haloalkyl, CF₃, cyano, hydroxy, ornitro.
 3. The compound as defined in claim 1 wherien

includes 1 to 3 heteroatoms.
 4. The compound as defined in claim 1wherein

is a 5-membered heteroaryl group or a 5-membered cycloheteroalkyl group.5. The compound as defined in claim 1 wherein

is a heteroaryl group.
 6. The compound as defined in claim 1 wherein

where R⁸ is selected from H, alkyl, haloalkyl, hydroxyalkyl,alkoxyalkyl, alkenyl, and R⁹ is selected from H, alkyl, alkenyl, formyl,CO₂(lower alkyl), hydroxyalkyl, alkoxyalkyl, CO(alkyl), carboxyalkyl,haloalkyl, alkenyl or cycloalkyl.
 7. The compound as defined in claim 6wherein


8. The compound as defined in claim 1 wherein R¹ and R² are the same ordifferent and are independently selected from aryl, cycloalkyl,heteroaryl or hydrogen.
 9. The compound as defined in claim 1 wherein R¹and R² are the same or different and are independently selected fromphenyl, cyclohexyl, hydrogen or pyrido.
 10. The compound as defined inclaim 1 wherein R³ and R⁴ are the same or different and areindependently selected from hydrogen, alkyl or halogen.
 11. The compoundas defined in claim 1 wherein —X—Z is


12. The compound as defined in claim 1 wherein

where R⁸ is H, lower alkyl, fluoroalkyl, or alkoxyalkyl, and R⁹ is H,lower alkyl, fluoroalkyl, alkoxy or hydroxyalkyl; R¹ and R² are the sameor different and are independently selected from phenyl or substitutedphenyl; R³ and R⁴ are the same or different are independently selectedfrom H, halo, alkyl or alkoxy; X is OCH₂, NHCH₂, CH₂ or CH₂CH₂; and Z isCO₂H or tetrazole.
 13. The compound as defined in claim 1 where

where R⁸ is H, lower alkyl or fluoroalkyl, and R⁹ is H, lower alkyl,fluoroalkyl, or alkoxy; R¹ and R² are each phenyl; R³ and R⁴ are each H;X is OCH₂, CH₂ or NHCH₂; and Z is CO₂H or tetrazole.
 14. The compound asdefined in claim 1 wherein

R³ is H R⁴ is H and —X—Z is


15. The compound as defined in claim 1 which is


16. The compound as defined in claim 1 which is


17. A pharmaceutical composition comprising a compound as defined inclaim 1 and a pharmaceutically acceptable carrier therefor.
 18. Apharmaceutical combination comprising an aP2 inhibitor compound asdefined in claim 1 and an antidiabetic agent other than an aP2inhibitor, an anti-obesity agent, a lipid-lowering agent, ananti-hypertensive agent, an anti-platelet agent and/or an anti-infectiveagent.
 19. The pharmaceutical combination as defined in claim 18comprising said aP2 inhibitor compound and an antidiabetic agent. 20.The combination as defined in claim 19 wherein the antidiabetic agent is1, 2, 3 or more of a biguamide, a sulfonyl urea, a glucosidaseinhibitor, a PPAR γ agonist, a PPAR α/γ dual agonist, an SGLT2inhibitor, a DP4 inhibitor, an insulin sensitizer, a glucagon-likepeptide-1 (GLP-1), insulin and/or a meglitinide.
 21. The combination asdefined in claim 20 wherein the antidiabetic agent is 1, 2, 3 or more ofmetformin, glyburide, glimepiride, glipyride, glipizide, chlorpropamide,gliclazide, acarbose, miglitol, pioglitazone, troglitazone,rosiglitazone, insulin, G1-262570, isaglitazone, JTT-501, NN-2344,L895645, YM-440, R-119702, AJ9677, repaglinide, nateglinide, KAD1129,AR-H039242, GW-409544, KRP297, AC2993, LY315902, and/or NVP-DPP-728A.22. The combination as defined in claim 19 wherein the compound ispresent in a weight ratio to the antidiabetic agent within the rangefrom about 0.01 to about 100:1.
 23. The combination as defined in claim18 wherein the anti-obesity agent is a beta 3 adrenergic agonist, alipase inhibitor, a serotonin (and dopamine) reuptake inhibitor, athyroid receptor beta compound, and/or an anorectic agent.
 24. Thecombination as defined in claim 23 wherein the anti-obesity agent isorlistat, ATL-962, AJ9677, L750355, CP331648, sibutramine, topiramate,axokine, dexamphetamine, phentermine, phenylpropanolamine, and/ormazindol.
 25. The combination as defined in claim 18 wherein the lipidlowering agent is an MTP inhibitor, an HMG CoA reductase inhibitor, asqualene synthetase inhibitor, a fibric acid derivative, an upregulatorof LDL receptor activity, a lipoxygenase inhibitor, or an ACATinhibitor.
 26. The combination as defined in claim 25 wherein the lipidlowering agent is pravastatin, lovastatin, simvastatin, atorvastatin,cerivastatin, fluvastatin, nisvastatin, visastatin, fenofibrate,gemfibrozil, clofibrate, avasimibe, TS-962, MD-700, and/or LY295427. 27.The combination as defined in claim 25 wherein the aP2 inhibitor ispresent in a weight ratio to the lipid-lowering agent within the rangefrom about 0.01 to about 100:1.
 28. The combination as defined in claim18 wherein the anti-hypertensive agent is an ACE inhibitor, avasopeptidase inhibitor, an angiotensin-II antagonist, a calcium-channelblocker, an alpha-blocker, a beta-blocker, a potassium channel opener, acentrally acting alpha agonist, and/or a diuretic.
 29. The combinationas defined in claim 28 wherein the anti-hypertensive agent isomapatrilat,[S-(R*,R*)]-hexahydro-6-[(2-mercapto-1-oxo-3-phenylpropyl)amino]-2,2-dimethyl-7-oxo-1H-azepine-1-aceticacid, lisinopril, enalapril, quinapril, benazepril, fosinopril,ramipril, captopril, enalaprilat, moexipril, trandolapril, perindopril,losartan, valsartan, irbesartan, candesartan, telmisartan, amlodipine,diltiazem, nifedipine, verapamil, felodipine, nisoldipine, isradipine,nicardipine, terazosin, doxazosin, prazosin, nadolol, propranolol,metoprolol, atenolol, carvedilol, sotalol, hydrochlorthiazide,torasemide, furosemide, spironolactone, indapamide, clonidine and/orguanfacine.
 30. The combination as defined in claim 18 wherein theanti-platelet agent is aspirin, clopidogrel, ticlopidine, abciximab,tirofiban, eptifibatide, anagrelide and/or dipyridamole.
 31. Thecombination as defined in claim 18 wherein the anti-infective isazithromycin, gatifoxacin, ciprofloxacin, levofloxacin, ortrovafloxacin.
 32. A method for treating insulin resistance,hyperglycemia, hyperinsulinemia, or elevated blood levels of free fattyacids or glycerol, obesity, hypertriglyceridemia, Syndrome X, diabeticcomplications, or atherosclerosis which comprises administering to amammalian species in need of treatment a therapeutically effectiveamount of a pharmaceutical composition as defined in claim
 17. 33. Amethod for treating Crohn's disease, ulcerative colitis, rheumatoidarthritis, chronic obstructive pulmonary disease, emphysema or systemiclupus erythematosis, which comprises administering to a human patient inneed of treatment a therapeutically effective amount of a compound asdefined in claim
 1. 34. A method for treating Crohn's disease,ulcerative colitis, rheumatoid arthritis, chronic obstructive pulmonarydisease, emphysema, or systemic lupus erythematosis, which comprisesadministering to a human patient in need of treatment a therapeuticallyeffective amount of a compound which inhibits aP2.